Access to this full-text is provided by Springer Nature.
Content available from Stem Cell Research & Therapy
This content is subject to copyright. Terms and conditions apply.
Shokravietal. Stem Cell Research & Therapy (2022) 13:192
https://doi.org/10.1186/s13287-022-02825-z
REVIEW
Mesenchymal stromal cells (MSCs)
andtheir exosome inacute liver failure (ALF):
acomprehensive review
Samin Shokravi1, Vitaliy Borisov2, Burhan Abdullah Zaman3, Firoozeh Niazvand4, Raheleh Hazrati5,
Meysam Mohammadi Khah6, Lakshmi Thangavelu7, Sima Marzban1*, Armin Sohrabi8,9 and Amir Zamani10*
Abstract
Recently, mesenchymal stromal cells (MSCs) and their derivative exosome have become a promising approach in the
context of liver diseases therapy, in particular, acute liver failure (ALF). In addition to their differentiation into hepato-
cytes in vivo, which is partially involved in liver regeneration, MSCs support liver regeneration as a result of their
appreciated competencies, such as antiapoptotic, immunomodulatory, antifibrotic, and also antioxidant attributes.
Further, MSCs-secreted molecules inspire hepatocyte proliferation in vivo, facilitating damaged tissue recovery in ALF.
Given these properties, various MSCs-based approaches have evolved and resulted in encouraging outcomes in ALF
animal models and also displayed safety and also modest efficacy in human studies, providing a new avenue for ALF
therapy. Irrespective of MSCs-derived exosome, MSCs-based strategies in ALF include administration of native MSCs,
genetically modified MSCs, pretreated MSCs, MSCs delivery using biomaterials, and also MSCs in combination with
and other therapeutic molecules or modalities. Herein, we will deliver an overview regarding the therapeutic effects
of the MSCs and their exosomes in ALF. As well, we will discuss recent progress in preclinical and clinical studies and
current challenges in MSCs-based therapies in ALF, with a special focus on in vivo reports.
Keywords: Mesenchymal stromal cell (MSCs), Exosome, Acute liver failure (ALF), Immunomodulation, Hepatocyte
© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the
original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or
other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line
to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this
licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco
mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Introduction
Acute liver failure (ALF) is characterized by the occur-
rence of coagulopathy (international normalized ratio
[INR] > 1.5) and any level of encephalopathy emerging
24weeks following the occurrence of the first symptoms
in patients who have no history of previous liver disease
[1]. e timing and the level of clinical presentation can
be classified into three types: hyperacute, acute, and sub-
acute [2]. Hyperacute and acute types involve fulminant
hepatic failure, while the subacute type is also named
subfulminant [3]. Interestingly, the mortality rate among
the patients whose hepatic encephalopathy appears
8weeks after the onset of symptoms (fulminant hepatic
failure) is lower than the patients with a more gradually
evolving course [4]. Multiorgan failure (MOF) has proved
to be the main cause of death (> 50%) from ALF, while
intracranial hypertension (ICH) and infection are the
other main causes of mortality in this patient population
[5].
During last two decades, a diversity of stem cells, such
as pluripotent stem cells (PSCs), mesenchymal stro-
mal cells (MSCs), hepatic progenitor cells (HPCs), and
hematopoietic stem cells (HSCs), has been used to treat
liver diseases [6–8]. However, MSCs are the most com-
mon type used in research, since they pose no ethical
Open Access
*Correspondence: Smarzban@larkinhospital.com; amir.zamani19800@gmail.
com
1 Department of Research and Academic Affairs, Larkin Community
Hospital, Miami, FL, USA
10 Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz,
Iran
Full list of author information is available at the end of the article
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 2 of 21
Shokravietal. Stem Cell Research & Therapy (2022) 13:192
challenges and can be obtained easily [9, 10]. Results
show that MSCs have the capability of differentiating
more than once; moreover, they can self-renew. ey
can differentiate into an array of cell lineages, including
hepatocyte-like cells (HLCs) [11]. MSCs are also charac-
terized by other properties, such as anti-inflammatory,
antiapoptosis, antifibrotic, antioxidant, blood vessel for-
mation, improvement of tissue repair, and growth factor
secretion [12, 13]. Despite many preclinical and clinical
investigations on MSCs used in treating ALF, it is still
unknown what mechanism contributes to the therapeutic
effect of MSCs. Besides, MSCs-exosomes have caught the
attention of many researchers as a new cell-free method
regarding the regeneration of the liver [14, 15]. ey have
dissipated the worries concerning the direct application
of MSC (e.g., immunogenicity and tumor formation [16].
Such exosomes encompass high frequencies of cytoplas-
mic and membrane proteins, including enzymes, tran-
scription factors, lipids, ECM proteins. ey also include
nucleic acids, such as mitochondrial DNA (mtDNA),
single-stranded DNA (ssDNA), double-stranded DNA
(dsDNA), messenger RNA (mRNA), and microRNA
(miRNA) [17]. e size of exosomes varies from 30 to
150nm, and they can be transferred to other cells to do
their functions. As a highly controlled process, the gen-
eration of exosome from the other organisms similar to
themselves is comprised of three main steps: (1) forma-
tion of endocytic vesicles by the folding of the exterior
area of the plasma membrane, (2) formation of multive-
sicular bodies (MVBs) by inward budding of the endo-
somal membrane, and (3) incorporation of established
MVBs with the plasma membrane and secretion of the
vesicular contents, called exosomes [14, 18]. Exosomes
elicit antioxidant effects and motivate target cells to trig-
ger downstream signals. Moreover, they convey genetic
material to target cells, leading to the suppression of
inflammation and apoptosis. [19, 20].
is review aims to give an overview of the present
knowledge to elucidate mechanisms used by MSCs to
underlie liver restoration in ALF. Another aim is to pre-
sent a discussion of new developments in preclinical and
clinical investigations on MSCs therapy in liver-associ-
ated diseases, with a particular focus on ALF.
Pathophysiology ofALF
Acetaminophen (APAP) has proved to be the main
cause of ALF [21]. e following people are highly likely
to experience ALF stimulated by APAP: alcoholic peo-
ple who use APAP; people who suffer from malnutri-
tion; or people who take medications that are believed
to induce CYP450 enzymes (e.g., phenytoin, carbamaz-
epine, or rifampin). Results of a study on 308 patients
with severe liver disorder in the USA revealed APAP as
the main cause of ALF in 40% of patients [22]. e other
causes detected were as follows in the increasing order of
prevalence:
• Malignancy (1%)
• Budd-Chiari Syndrome (2%)
• Pregnancy (2%)
• Wilson disease (3%)
• Hepatitis A virus infection (4%)
• Autoimmune hepatitis (4%)
• Ischemic hepatitis (6%),
• Hepatitis B virus infection (6%)
• Idiosyncratic drug-induced liver injury (13%)
e causes of 17 percent of cases were not known [4].
Based on results, it is possible to categorize the ALF
pathophysiology into two groups: pathophysiologies
of liver problems involving a specific cause and patho-
physiology concerning the appearance of second-
ary multiorgan failure (MOF) [23]. With regard to the
pathophysiology of liver disorders, the results show that
APAP toxicity is the main cause [24]. Secondary MOF
often derives from the primary extensive pro-inflam-
matory effect, which leads to a pervasive inflammatory
effect syndrome. en, a deregulated anti-inflammatory
response ensues [25, 26].
It is not clear what mechanism causes the ongoing
death of tissue when there is no ongoing injury. Oxida-
tive stress results in the formation of reactive oxygen
species (ROS). This, in turn, activates c-Jun N-termi-
nal kinase (JNK) through a series of events [27]. Such
activation may support disruption of normal mito-
chondrial function, which inspires more hepatocyte
necrosis and damage associated molecular patterns
(DAMPs) [28, 29]. DAMPs bring about the activation
of hepatic macrophages, resulting in the formation of
the inflammasome [30, 31]. Concisely, as complexes
characterized by multiple proteins, inflammasomes
receive the intracellular danger signals through NOD-
like receptors (NLRs) [32]. The inflammasome effec-
tively regulates the inflammatory response by eliciting
a response to low-threshold signals. Toll-like receptors
(TLRs) induction by DAMPs leads to the inflamma-
some activation, supporting the subsequent activation
of caspase-1 and IL-1β secretion [33, 34]. Researchers
have identified the characteristics of the NLR family
pyrin domain containing 3 (NLRP3) inflammasome
belonging to the inflammasome family. NLRP3 inflam-
masome has three potential activation pathways: (1)
ATP signal which occurs outside a cell, leading to
potassium efflux and pannexin recruitment; (2) incor-
poration of crystalized cholesterol, uric acid or amy-
loid with lysosomal dysfunction after the ingestion and
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 3 of 21
Shokravietal. Stem Cell Research & Therapy (2022) 13:192
elimination of these particles; and (3) activation by
reactive oxygen species (ROS) [33, 35, 36]. Investiga-
tions have examined the activation of inflammasome
in APAP-induced ALF by a special focus on the con-
tribution of the inflammasome to acute liver disorder
[37]. It appears that DAMPs are released from necrotic
hepatocytes and sinusoidal endothelial cells, leading
to the activation of the inflammasome in the manner
mentioned above.
The rationality ofMSCs therapy inALF
MSCs migration to damage tissue by interaction with
several receptors and molecules, and thereby inducing
liver recovery by various mechanisms has been proved
(Fig.1). Although the mechanisms of MSCs transplanta-
tion are still not entirely understood, a growing body of
proof has indicated that their immunomodulation, differ-
entiation, and antifibrotic capabilities play central roles in
liver repair. Among them, anti-inflammatory potential of
MSCs play most critical role. Although there is no clear
Fig. 1 Underlying mechanism complicated in mesenchymal stromal cells (MSCs) migration to damaged liver tissue. The connections between
CXCR4 and SDF-1ɑ, c-Met and HGF, and finally VLA-4 and VCAM-1 underlie cell to cell interaction between endothelial cells (ECs) and MSCs, which,
in turn, facilitate MSCs migration to damaged liver tissue. Then MSCs secrete anti-inflammatory molecules, such as PGE2, IDO, TGF-β, IL-10, and NO
to down-regulate inflammation. These molecules prompt the change of inflammatory to proliferating phase largely defined by the secretion of
PDGF and VEGF, sustaining hepatocyte formation and proliferation
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 4 of 21
Shokravietal. Stem Cell Research & Therapy (2022) 13:192
evidence indicating the MSCs invivo differentiation into
hepatoid cells post-transplantation, MSCs can be differ-
entiated into hepatocyte-like cells (HLCs) in vitro and
then be infused. Of course, this process is time-consum-
ing process with insufficient established HLCs, thereby
hindering its therapeutic utility in clinic. However, there
is some evidence indicating that replacing fetal bovine
serum (FBS) with polyvinyl alcohol (PVA) might lead
to improved differentiation ability [38]. Invivo, as only
a small number of intravenously injected cells reach the
liver, MSCs-mediated favored effects mainly depend on
the secreted molecules rather than their direct effects
or differentiation into hepatocytes post-transplantation
[39].
MSC anti‑inammatory properties
e hepatocyte loss is the first symptom and mechanism
contributing to acute liver damage. It is still unclear what
causes ongoing necrosis when there is no injury. ROS are
produced in response to oxidative stress. is, in turn,
activates c-Jun N-terminal kinase (JNK) through a series
of events, resulting in mitochondrial dysfunctions. ese
events lead to a higher level of hepatocyte necrosis, as
well as the expansion of DAMPs [40]. DAMPs stimulate
the activation of hepatic macrophages and the formation
of the inflammasome [41]. In the next stage, the release
of pro-inflammatory cytokines eases the recruitment of a
larger number of immune cells to the inflammation area,
and so advances hepatocyte cell necrosis.
e majority of past investigations have indicated that
MSCs play a therapeutic role in the treatment of liver
dysfunction by releasing trophic factors and the factors
modulating the immune system [42]. Although the role
of MSCs in modulating the immune system is unclear,
they might control the immune cells through the secre-
tion of soluble factors and the contacts between cells. e
regulation of adaptive and innate immune responses by
MSCs is exerted by inhibiting T cells and dendritic cells
(DCs), which leads to a reduction in the activation and
growth of B cells [43, 44]. is, in turn, enhances the
formation of regulatory T (Treg) cells and prevents the
growth and toxicity of natural killer (NK) cells induced by
the chemotherapeutic molecules [45]. Also, transforming
growth factor-beta (TGF-β) and interleukin 10 (IL-10)
as crucial factors in the regulation of a large number of
inflammatory cells [46, 47]. Studies revealed a significant
increase in the amounts of TGF-β and IL-10 in serum
following the injection of UC-MSCs, but a significant
decrease in the amounts of IL-6, tumor necrosis factor-
alpha (TNF-α), and cytotoxic T lymphocytes (CTLs) was
seen in peripheral blood [48]. is led to the restoration
of liver function, as well as a reduction in the develop-
ment of disease and the level of mortality. Furthermore,
transient T cell apoptosis can be induced by BM-MSCs
through the Fas ligand (FasL)-dependent pathway [49].
en, macrophages are stimulated by apoptotic T cells
to form high amounts of TGF-β, resulting in the up-reg-
ulation of Treg cells to trigger immune tolerance. MSCs
can prevent cytotoxic CTLs and NK cells through the
contact between cells and paracrine factors, including
indoleamine 2,3-dioxygenase (IDO), TGF-β, and prosta-
glandin E2 (PGE2) [50, 51]. Of course, TGF-β acts as a
two-edged sword. It can weaken the immune system and
thereby suppress liver inflammation [49]; on the other
hand, it can increase liver fibrosis [52]. MSCs, in fact,
can act as an immunomodulatory agent in reducing the
inflammation of the body through up-regulating anti-
inflammatory Treg cells and decreasing T helper 1 (1)
and 17 cells in ALF [53]. Moreover, the inflammation
after MSC transplantation can be indirectly stimulated
by up-regulating M2-type macrophages, leading to the
secretion of a variety of anti-inflammatory factors, such
as chemokine ligand 1 (CCL-1) and IL-10, up-regulation
2, and Treg cells [54]. Also, MSCs play an important
role in the reduction of B-cell growth through contact
between cells and the secretion of soluble factors [55].
Finally, MSC transplantation can play an effective role in
mitigating liver damage in ALF by decreasing the number
and activity of neutrophils in both peripheral blood and
the liver.
MSCs dierentiate intoHLCs
MSCs are characterized by their ability to proliferate and
differentiate invitro. For the first time, Friedenstein etal.
procured MSCs in 1968 from the bone marrow (BM) [56,
57]. After that, MSCs obtained from multiple sources,
making them an excellent supply of multipotent cells for
treatment of liver dysfunctions. A variety of methods are
used to differentiate MSCs into HLCs [58, 59]. Studies
show that multiple signals contribute to the regulation
of the cells’ behavior in a cooperative manner. Such sig-
nals are usually triggered by extracellular matrix (ECM),
growth factors, and even juxtacrine signals [60]. Each one
of the organs, as well as the developmental stage, is char-
acterized by a specific regulated timing and distribution
pattern of signals. As a result, achieving better results
in the case of in vitro cultures requires establishing a
type of environment that resembles the local environ-
ment. Based on the research previously done, it is pos-
sible to differentiate MSCs obtained from various sources
into hepatocytes in the case of both mice and humans
through the implementation of a variety of protocols and
methods invitro [61, 62].
Hepatic differentiation protocol is known to be the
most frequently used method for hepatic differentia-
tion, which benefits from Iscove’s Modified Dulbecco’s
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 5 of 21
Shokravietal. Stem Cell Research & Therapy (2022) 13:192
Medium (IMDM), as well as cytokine cocktail. Epider-
mal growth factor (EGF) or fibroblast growth factors
(FGF) trigger the MSCs to differentiate into endoder-
mal cells during the early induction stage. EGF prompts
the MSCs to proliferate by interfaces with EGF receptor
(EGFR) [63]. Besides, FGF is a member of a bigger fam-
ily that is comprised of seven polypeptides with similar
characteristics [64]. is family plays an essential role
in the primary stage of endodermal patterning [65].
In particular, FGF-4 and basic FGF (bFGF) are com-
monly used. Like EGF, FGF influences the growth rate
of MSCs [66].
Generally, the differentiation of cells is stimulated
by adding FGF, HGF, nicotinamide (NTA), and also
insulin-transferrin-selenium (ITS) into cultures [67].
As a mesenchymal origin pleiotropic cytokine, hepato-
cyte growth factor (HGF) contributes to adjustment of
growth, differentiation, and chemotactic migration of
MSCs [68]. MSCs’ exposure to HGF for a short time
causes the activation of c-Met receptors along with
its downstream agents such as extracellular signal-
regulated protein kinase (ERK)1/2, p38, mitogen-acti-
vated protein kinases (MAPKs), and phosphoinositide
3-kinase (PI3K) /Akt [69, 70]. MSCs’ exposure to
HGF for a long time will make changes in cytoskeletal
arrangement; moreover, it results in the migration of
cells and a notable decrease in proliferation. In addi-
tion, ITS and NTA promote the growth and survival of
primary hepatocytes [71].
Despite the fact that MSCs can differentiate in culture
through induction, the organ-specific microenvironment
is the best technique, enabling MSCs differentiation into
a certain cell type. e ability to express hepatocyte-
specific genes is one of the specific characteristics of
hepatic-differentiated cells, which can be affected by
microenvironmental features [72]. Reports display that
in the case of humans, the differentiation of the MSCs
obtained from umbilical cord (UC) into HLCs occurs
more quickly in the fibrotic liver microenvironment [73].
Other studies also show that the differentiation of
MSCs into functional hepatocytes does not occur
directly; rather, these cells initially differentiate into bil-
iary epithelial cells (BEC)-like cells, followed by differen-
tiation into HLCs [74]. However, according to the results
of other investigations, MSCs transdifferentiation infre-
quently occurs after MSC infusion in animal models
[75]. MSCs obtained from menstrual blood, for instance,
turned out to prevent hepatic satellite cells (HSCs) acti-
vation and resultant liver fibrosis, leading to the improve-
ment of liver function. Yet, very few transplanted MSCs
differentiated into functional HLCs in vivo [76]. ese
results demonstrate that the therapeutic impact of MSCs
is mediated mainly by indirect paracrine signaling.
MSCs antibrotic properties
anks to their antifibrotic and immunosuppressive
properties, MSCs play an important role in the treatment
of fibrosis [77]. Also, fibrosis in not a common pathologi-
cal signs of ALF; long-term liver damage mainly results
in fibrosis. MSC transplantation could attenuate liver
fibrosis by down-regulation of TGF-β1, Smad2, collagen
type I, and smooth muscle alpha-actin (αSMA), reduc-
ing liver fibrosis regions invivo [78]. Besides, BM-MSCs
decreased hepatic collagen distribution by impairing the
TGF-β/Smad signaling pathway in a cirrhosis rat models
[79]. MSCs also ameliorated hepatic microvascular dys-
function and portal hypertension, which contribute to
complications defining clinical decompensating [80]. Fur-
ther, the expression of matrix metalloproteinase (MMP)-
2, -9, -13, and -14 can be up-regulated by MSCs [81],
which, in turn, attenuates liver fibrosis through degrad-
ing extracellular matrix (ECM) [82]. MSCs reinforce this
effect by the down-regulation of the tissue inhibitors of
matrix metalloproteinases (TIMPs). Importantly, there is
an association between the balanced levels of MMPs and
TIMP and fibrosis resolution [83]. Moreover, MSCs have
both direct and indirect roles in inhibiting the activation
and growth of hepatic satellite cells (HSCs) and thereby
could inhibit collagen synthesis [84]. e direct inter-
actional relationship between MSCs and HSCs helps to
inhibit HSC proliferation by stimulating G0/G1 cell-cycle
arrest. is is done by inhibiting the phosphorylation of
ERK1/2 [85]. On the other hand, MSCs contain substan-
tial levels of milk fat globule-EGF factor 8 (MFGE8). e
MFGE8 reduces expression levels of TGF-β1 receptor on
HSCs, thus strikingly fences primary human HSCs acti-
vation [86]. In co-culture conditions, MSCs also mainly
impair α-smooth muscle actin (α-SMA) expression of
HSCs, which is mediated, in part, by the activation of the
Notch pathway [87]. e indirect secretion of some piv-
otal factors (IL-10, HGF, TGF-β, and TNF-α) by MSCs
averts the growth of HSCs and reduces the formation of
collagen. In contrast, HGF and NGF enhance the apopto-
sis of HSCs [88, 89].
MSCs antioxidant properties
One of the events deriving from ROS is oxidative stress,
which is known as a common driver in creating dam-
age to the liver. Some of these damages include the
liver failure, liver fibrosis, liver cirrhosis, viral hepatitis,
and also hepatocellular carcinoma (HCC) [90, 91]. e
results of some investigations have revealed that MSCs
play a strong mediatory antioxidant role in different
animal models [92, 93]. Oxidative liver injury is mostly
caused by thioacetamide (TAA) or carbon tetrachloride
(CCl4) as the most commonly used toxins. ese types
of toxins give rise to hepatocyte dysfunction through
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 6 of 21
Shokravietal. Stem Cell Research & Therapy (2022) 13:192
the peroxidation of lipid and proteins alkylation, nucleic
acids, and lipids [94, 95], resulting in the inflammatory
response, hepatocellular injury, and liver fibrosis. Cell
signaling and homeostasis require a low level of physi-
ologic ROS formed by the mitochondrial respiration.
MSCs have proved to have the capability of mitigating
oxidative stress simulated by CCl4 and TAA invivo [96,
97]. rough enhancing the superoxide dismutase (SOD)
expression and antioxidant response elements (AREs)
stimulation, MSCs boost antioxidant and cytoprotective
performance, leading to a reduction in hepatocyte apop-
tosis [98, 99]. Due to their antioxidant role along with
their role in modulating the immune systems, MSCs can
be very useful in developing therapies for liver injuries.
The importance ofMSCs‑exosome ascell‑free
approach inALF
Exosome is a main subtype of extracellular vesicles (EVs)
with a diameter in the range of 40–150 nm. Exosome
are mainly produced by a diversity of human cells, such
as stem/stromal cells, immune cells, and tumor cells
[100]. ey include several biological components, more
importantly, miRNAs, proteins, lipids and mRNAs, as
cargo [101, 102]. e production and secretion proce-
dure of exosome consists of three chief steps: (1) crea-
tion of endocytic vesicles through invagination of the
plasma membrane, (2) creation of multivesicular bodies
(MVBs) upon endosomal membranes’ inward budding,
and (3) incorporation of created MVBs with the plasma
membrane and releases of the vesicular contents termed
exosomes [14, 18]. en, the contents of exosomes are
transferred to the recipient cells, and thereby modify
physiological cells [15]. As a result of their great capa-
bilities to elicit hepatoprotective effect, exosomes are
recently been considered as a rational therapeutic option
for liver failure, thereby circumventing comprehensions
concerning stromal cells’ direct transplantation [103,
104]. ey are smaller and less complex compared with
parent cells, and thereby easier to produce and store.
Also, they exhibit no risk of tumor formation. Impor-
tantly, exosomes are less immunogenic than their par-
ent cells due to their lower membrane-bound proteins.
Recently, UC-MSCs-derived glutathione peroxidase1
(GPX1) enriched exosome showed the capacity to com-
promise oxidative stress as well as apoptosis in the hepat-
ocyte, stimulating hepatoprotective effect in ALF rodent
models [105]. Also, MSCs-derived exosome potently
reduced inflammatory response in ALF animal models
by impairment of IL-6-mediated signaling axis [106] and
also down-regulation of NLRP3 pathway [107]. However,
further studies are strongly needed to entirely elucidate
how MSCs-derived exosomes exert their hepatoprotec-
tive influences invivo.
MSCs inALF (animal studies)
Native MSCs
MSCs-based treatments have shown huge potential for
regenerating the liver and repairing its injury, which
resulted from several liver disorders (Tables1, 2). Invivo,
MSCs can migrate to damaged tissues and constrain the
production of pro-inflammatory molecules (e.g., IL-1,
IL-6, and TNF-ɑ) and ultimately potentiate liver cells
growth. As described, the chief mechanism behind the
MSCs-mediated positive effects is their immunoregula-
tory potential rather than direct differentiation into hap-
toid cells. ese cells efficiently hinder the activation of
both innate and adaptive immune system cells, such as
neutrophils, macrophages, NK cells, DCs, monocytes,
and also lymphocytes. Studies in liver failure animal
models revealed that MSCs could transdifferentiate into
albumin-expressing HLCs, and also may support nor-
mal hepatocytes proliferation in vivo upon fusion with
them [108]. Findings have outlined the important roles of
SDF-1/CXCR4 axis to ease MSCs migration to damaged
tissue, sustaining liver rescue in ALF [108]. As well, injec-
tion of MSCs-derived hepatocyte into mice with liver fail-
ure ameliorated liver function, as evidenced by analysis of
serum profile as well as biochemical factors rates [109].
Notably, the serum levels of TGF-β1 and IL-10 in trans-
planted animals were more prominent than in control
animals [109]. Other studies displayed that pyroptosis, a
unique shape of programmed cell death induced by pen-
etrating inflammatory reaction, was suppressed by MSCs
therapy in ALF preclinical model [110]. Accordingly,
MSCs administration caused liver repair in C57BL/6 mice
by up-regulation of IL-10 and concomitantly suppression
of NLRP3 [110]. Given that NLRP3 inflammasome elicits
liver failure through induction of procaspase-1 and pro-
IL-1 β accompanied with the adjustment of downstream
CD40-CD40L signaling, its inhibition as elicited by MSCs
can enable liver recovery in ALF [111]. Besides, the study
of the soluble factor produced by MSCs and their potent
desired impacts in a rat model of ALF revealed that
IL-10, which mainly is secreted by MSCs, has a central
role in ALF recovery post-transplantation [112]. It was
found that phosphorylated STAT3 diminished upon
IL-10 injection and conversely STAT3 suppression abro-
gated IL-10-induced effects in vivo, reflecting the emi-
nent role of STAT3 signaling in exerting IL-10-induced
anti-inflammatory influences [112]. In addition to the
IL-10, MSC-produced PGE2 could constrain apoptosis
and simultaneously augment hepatocyte proliferation,
thereby decreasing ALF [113]. In fact, PGE2 stimulated
YAP activation and then activated YAP suppressed phos-
phatase and tensin homolog (PTEN) and consequently
up-regulated mammalian target of rapamycin (mTOR),
a foremost controller of cell growth. is axis in turn
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 7 of 21
Shokravietal. Stem Cell Research & Therapy (2022) 13:192
protected versus ALF through increasing hepatocyte
proliferation [113]. Furthermore, there is clear evidence
signifying that MSCs could modify phenotype and func-
tion of macrophages, adjust DCs either differentiation or
maturation, and impede the T cell activities by the pro-
duction of tumor necrosis factor-alpha-stimulated gene 6
(TSG-6) in ALF models [114]. TSG-6 mainly averts the
inflammatory response as a result of suppressing P38 and
JNK signaling axes, providing a suitable milieu for ALF
rescue upon MSCs transplantation [115]. MSCs also can
induce their favored influences by heme oxygenase (HO)
1, a rate-limiting enzyme in heme metabolism, which is
noted as an effective antioxidative and cytoprotective
molecule. Recently, it was proven that MSCs administra-
tion gave rise to HO-1 up-regulation, whereas suppress-
ing HO-1 impaired MSCs-induced desired effects and
also hepatocyte autophagy [116]. ese favored effects
upon MSCs therapy were most probably caused by PI3K/
Akt signaling pathway-induced HO-1 up-regulation
[116]. Also, Zhang etal. found that systemic administra-
tion of BM-MSCs into the ALF rat model attenuated ALF
by up-regulation of the HO-1 expression and subsequent
attenuation in neutrophil infiltration and activation [117].
is event finally reduced hepatocyte apoptosis and also
improve their proliferation, culminating liver recovery.
Similarly, the pivotal role of neutrophils in ALF patho-
genesis has been clarified by other reports [118]. In the
D-galactosamine-induced ALF animal model, the great
number of neutrophils aggregated in the liver tissue along
with promoted myeloperoxidase (MPO) activity and
enhanced alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) serum levels are mainly detected
[118]. Nonetheless, injection of BM-MSCs brought
about functional recovery, which was documented by
reduced ALT and AST levels and also improved sur-
vival rate in the treatment group compared with the
Table 1 Direct administration of native mesenchymal stromal cells (MSCs) in liver failure preclinical models, especially acute liver
failure (ALF)
Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Glycogen synthase kinase-3β (GSK-3β), Mammalian target of rapamycin (mTOR), Phosphoinositide
3-kinases (PI3Ks), CXC chemokine receptor 4 (CXCR4), Stromal derived factor-1α (SDF-1α or CXCL12), Prostaglandin E2 (PGE2), Nuclear factor-erythroid factor 2-related
factor 2 (Nrf2), Nuclear factor-kappa B (NF-κB), Natural killer T (NKT ) cells, T helper 17 (Th17), Interleukin-10 (IL-10)
Sources Model Result (ref)
Placenta Rat Migration to damaged site and induction of immunomodulatory effects by secreting paracrine factors in ALF [193]
Bone marrow Rat Systemic administration of MSCs reduced ALT, AST, and bilirubin levels [124]
Bone marrow Rat Reducing ALF, improving glucose metabolism and survival, and also stimulation of the hepatocyte proliferation by activating
AKT/GSK-3β/β-catenin pathway [122]
Adipose tissue Rat Normalization of amino acids, sphingolipids, and glycerophospholipids in the liver and blood along with attenuation hepato-
cyte apoptosis and conversely promoting their proliferation rate [194]
Placenta Rat Stimulation of liver repair through the antifibrotic and autophagic mechanisms [149]
Umbilical cord Monkey Inhibition of the activity of IL-6 producing monocyte, amelioration of the liver histology, and also animal survival [119]
Adipose tissue Rat Suppression of the secondary complications of liver failure [195]
Bone marrow Porcine Improving the liver function homeostasis, attenuation of reactive oxygen species (ROS) following efficient homing, and also
differentiation into hepatocytes [196]
Bone marrow Rat Amelioration of mitochondrial activities and normalization of lipid metabolism upon modifying the mTOR pathway [197]
Umbilical cord Rat Provoking the endogenous liver regeneration, hindrance of hepatocyte apoptosis by up-regulated c-Met in hepatocyte [120]
Bone marrow Rat Potentiating of MSCs-elicited liver regeneration following the abrogation of autophagy in MSCs [198]
Bone marrow Rat Amelioration of ALF by up-regulation of the heme oxygenase 1 (HO-1) expression, which resulted in inspiring the autophagy
process through PI3K/AKT signaling axis [116]
Bone marrow Mice Enhancing MSCs competencies to stimulate liver recovery following transdifferentiation as well as fusion with hepatocytes
by SDF-1/CXCR4 axis [199]
Bone marrow Mice Reducing ALF by IL-10 produced by MSCs, which ultimately inhibits pyroptosis [110]
Bone marrow Mice MSCs derived from adipose tissue showed superiority over MSCs isolated from bone marrow in ALF [125]
Bone marrow Mice Improvement of hepatocyte mediated by PGE2 released by MSCs, ameliorating ALF [113]
Wharton’s jelly Mice Restoration of hepatotoxicity by WJ-MSC [200]
Bone marrow Swine Averting ALF upon stimulation of hepatocyte proliferation and suppressing their apoptosis by intraportal MSCs transplanta-
tion [123]
Bone marrow Rat Attenuated aggregation and function of neutrophils [118]
Adipose tissue Mice Protection against ALF by affecting the Nrf2 and cytochrome P450 expression [201]
Umbilical cord Mice Inducing the endogenous liver regeneration but not notable hepatogenic differentiation [202]
Umbilical cord Mice Attenuation of ALF by down-regulation of MyD88/NF-κB pathway involved in inflammation [203]
Bone marrow Mice Attenuation of ALF by modifying ratio between Th17 and regulatory NKT cells [204]
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 8 of 21
Shokravietal. Stem Cell Research & Therapy (2022) 13:192
control group (50% vs 12.5%). Notably, the intervention
led to a robust decrease in the population of neutro-
phils in the liver, MPO function, and also the expression
of pro-inflammatory factors, including TNF-α, IL-1β,
interferon gamma (IFNγ) and CXC chemokine ligands
1/2 (CXCL1/2) [118]. In addition, in a monkey model of
ALF, systemic administration of the MSCs derived from
another source, unbiblical cord (UC), reduced hepatic
aggregation and maturation of circulating monocytes and
their IL-6 releases, resulted in prolonged survival [119].
UC-MSCs also could induce a reduction in ALF by pro-
voking the endogenous liver regeneration in association
with suppression of liver cell apoptosis by up-regulating
HGF/c-Met signaling axis [120] or down-regulation of
Notch and STAT1/STAT3 signaling [121]. e positive
influences of MSC therapy on hepatocyte proliferation
also may arise from activation of AKT/ glycogen synthase
kinase 3 beta (GSK-3β)/β-catenin pathway and enhance-
ment in glucose metabolism leading to improved survival
rate in ALF animal model [122]. Interestingly, intraportal
injection of MSCs showed superiority over hepatic intra-
arterial, intravenous, and intrahepatic injection in terms
of liver recovery rate in swine with ALF. Notably, the liver
recovery might be attributable to down-regulation of
caspase-3, up-regulation of apoptosis inhibitor survivin
as well as activation of AKT and ERK axes [123]. On the
other hand, another study revealed that systemic infusion
of MSCs was more effective than the intraperitoneal (IP)
injection to support liver recovery because of the more
significant increase in expression levels of growth factor
vascular endothelium growth factor (VEGF) [124]. Also,
compared with BM-MSC, adipose tissue (AT)-derived
MSCs displayed higher therapeutic capacities, as defined
by estimation of ALT and AST levels post-transplanta-
tion in ALF murine model [125].
MSCs delivery using biomaterials
Present cell transplantation approaches are hindered
via poor post-delivery survival, liver ECM and vascula-
ture deterioration, and also difficulties in fusion into the
host tissue [126]. As a result, scientists are persuaded
to deliver MSCs within biomaterial structure to sustain
the transplants’ viability and also potentiate MSCs long-
standing activation invivo [126].
Recent reports noted that BM-MSCs are valued options
to co-culture with hepatocytes in poly (lactic acid-gly-
colic acid) (PLGA) scaffolds, enhancing the hepatocel-
lular activities [127]. Administration of BM-MSCs and
hepatocyte seeded PLGA scaffolds led to the considerably
advanced cellular proliferation and conversely supported
Table 2 Administration of modified mesenchymal stromal cells (MSCs) or/and native MSCs in combination with other modalities in
liver failure preclinical models, especially acute liver failure (ALF)
CXC chemokine receptor 4 (CXCR4), Interleukin-1 (IL-1), Hepatocyte nuclear factor 4 alpha (HNF4α), Transforming growth factor (TGF-β), Vascular endothelial growth
factor 165 (VEGF165), Granulocyte colony-stimulating factor (G-CSF), Hepatocyte growth factor (HGF)
Sources Model Intervention Result (ref)
Adipose tissue Rat MSCs plus Eugenol Enhancing antifibrotic competencies of MSCs by eugenol
through down-regulation of TGF-β/Smad axis [205]
Bone marrow Rat MSC plus
Neutrophil depletion Amelioration of ALF in rats [206]
Umbilical cord Rat MSC plus Icaritin Enhancing the antiapoptotic capability of MSCs by promot-
ing the HGF/c-Met pathway [131]
Umbilical cord Mice HNF4α-overexpressing MSCs plus Hepatocyte Improving the EGF release by HNF4α-UMSCs [207]
Umbilical cord blood Rat VEGF165 -overexpressing MSCs Induction of marked therapeutic influences on ALF [143]
Bone marrow Mice CXCR4-overexpressing MSCs Improved migration and reduced damaged tissue by
stimulating hepatoprotective impacts [142]
Amniotic fluid Rat IL-1-overexpressing MSCs Improved liver function along with prolonged survival [145]
NA Swine MSCs plus IL-lRa-loaded chitosan nanoparticles Eliciting a synergistic impact by abrogating liver inflamma-
tion [136]
Bone marrow Rat Dexmedetomidine and Midazolam primed MSCs Enhancing the therapeutic merits of MSCs [208]
Umbilical cord Rat MSCs plus G-CSF Attenuation of liver damage by suppressing the genera-
tion of pro-inflammatory cytokines, alleviation of oxidative
stress, and reducing liver cell loss [132]
Bone marrow Swine MSCs plus IL-1R antagonism Exerting synergistic influences by prohibiting the inflamma-
tion and apoptotic signaling [135]
Bone marrow Mice MSCs seeded on human amniotic membranes (HAM) Improving survival rate [209]
Bone marrow Mice Poly lactic-co-glycolic acid (PLGA) scaffold loaded with
MSCs Stimulation of hepatoprotective impacts by paracrine fac-
tors [127, 128]
Bone marrow Mice Regenerated silk fibroin (RSF) scaffold loaded with MSCs Potentiating liver function by provoking angiogenesis [130]
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 9 of 21
Shokravietal. Stem Cell Research & Therapy (2022) 13:192
a striking reduction in ALT, AST, and total bilirubin in
ALF preclinical models post-transplantation, ultimately
leading to the prolonged survival [127]. Another study
demonstrated that MSCs seeded PLGA scaffolds were
survived for 3weeks, and displayed more evident activi-
ties than MSCs injected by intravenous route, which was
verified by lower mortality invivo [128]. However, there
was no significant alteration in hepatic inflammation and
necrosis zones between the two applied interventions
[128]. Also, poly L-lactic acid (PLLA) nanofiber scaffold
could improve the hepatic differentiation of BM-MSCs
[129]. Invitro, analysis exhibited that expression levels
of liver-specific markers, more importantly, albumin and
α-fetoprotein, were greater in differentiated cells on the
nanofibers compared with differentiated cells in plates.
ese results deliver the proof of the theory that engi-
neered PLLA scaffold could be an efficient alternative
to augment MSCs differentiation into functional HLCs
[129]. Besides, BM- and AT-MSC seeded regenerated silk
fibroin (RSF) matrices potently differentiated into HLCs
in vitro and also stimulated angiogenesis and restored
liver functions in the ALF mice model invivo [130].
Combination therapy withMSCs
A diversity of studies recently has focused on combina-
tion therapy with MSCs and other molecules or modali-
ties to diminish ALF. Meanwhile, co-administration of
MSCs with Icaritin, a well-known ingredient isolated
from traditional Chinese medicine, resulted in promis-
ing outcomes in vivo [131]. Indeed, MSCs co-cultured
with Icaritin improved survival, reduced serum levels of
AST and ALT, and elicited histological variations in liver
tissue more potently than MSCs alone. Importantly, the
up-regulation of HGF/c-Met by Icaritin was found to be
involved in MSCs-triggered antiapoptotic influences on
hepatocytes, reflecting the potential of herbal extracts
to promote MSC-mediated therapeutic impacts [131].
e addition of the granulocyte colony-stimulating fac-
tor (G-CSF) to UCB-MSCs also improved survival and
reduced ROS and pro-inflammatory cytokines expres-
sions in ALF murine model [132]. Also, intervention
engendered a significant reduction in cell apoptosis in
liver tissues more evidently than UCB-MSCs alone [132].
ese findings were similar to previous reports display-
ing that G-CSF therapy alone could significantly attenu-
ate short-term mortality in patients suffering from liver
failure mainly by reducing inflammation concomitant
with activating PI3K/Akt axis in hepatocytes [133, 134].
In another study, thanks to the crucial role of IL-1 in
the progress of ALF, Sang etal. evaluated possible syn-
ergetic effects of combined use of MSCs with 2 mg/kg
interleukin-1 receptor antagonist (IL-1Ra) invivo [135].
ey found that treatment significantly attenuated liver
cell apoptosis, improved their proliferation, and even-
tually enhanced animal survival. It is supposed that the
observed effects were dependent on enhancement in
AKT and also a reduction in nuclear factor (NF)-κB
expression, potentiating liver cell proliferation [135].
Similarly, co-administration of MSCs plus IL-1Ra chi-
tosan nanoparticles (NPs) was more effective than MSC
transplantation alone for treating ALF [136]. IL-1Ra-
loaded NPs administration by ear veins exhibited syner-
gistic impacts with portal vein injection of MSC in a mini
swine model of ALF by the hindrance of liver inflamma-
tion [136].
Pretreated MSCs
Current studies have verified that pretreatment
with chemical agents, hypoxia, and also cytokine or
chemokine invitro can improve the therapeutic merits of
MSCs upon transplantation invivo [137, 138]. Compared
to native MSCs, pretreated MSCs largely demonstrate
developed hepatogenic differentiation, homing capability,
and survival and paracrine impacts.
In 2019, Nie etal. suggested that IL-1β pretreatment
could circumvent the MSC’s poor migration toward the
injured region in ALF murine model [139]. Correspond-
ingly, IL-1β-MSCs showed superiority over native MSCs
respecting the survival time and liver function in vivo.
Remarkably, IL-1β-MSCs suppressed liver cell apoptosis
and necrosis and also provoked their proliferation. Pre-
ferred effects were most probably enticed by improved
CXCR4 expression resulting from IL-1β pretreatment
and thereby increased migration toward CXCL12 (SDF-1
α) in damage tissue [139]. Interestingly, pretreatment
with injured liver tissue might improve MSCs homing
and also their hepatogenic differentiation [140]. Invivo,
transplantation of pretreated MSCs led to an enhance-
ment in albumin, cytokeratin 8, 18, and antiapoptotic
protein Bcl-xl levels, whereas supported a reduction in
pro-apoptotic protein Bax and caspase-3 levels [140].
Likewise, short-term, but not long-term, sodium butyrate
(NaB) treatment augmented hepatogenic differentiation
of BM-MSCs and consequently alleviated liver injury
invivo, according to Li etal. reports [141].
Genetically modied MSCs
Genetically modified MSCs mainly are used to enhance
their colonization rate post-transplantation, leading to
ameliorated liver recovery in ALF. Meanwhile, geneti-
cally modified MSC to overexpress the CXCR4 gene
demonstrated more appropriate migration capability
toward SDF-1α and also induce better hepatoprotective
impacts invitro [142]. In ALF murine model, CXCR4-
MSCs efficiently migrated to damaged tissue, and in
turn, brought about prolonged survival and restored
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 10 of 21
Shokravietal. Stem Cell Research & Therapy (2022) 13:192
liver activity more prominent than native MSCs trans-
plantation [142]. Besides, UCB-MSCs modified to
overexpress vascular endothelial growth factor 165
(VEGF165), a strong pro-angiogenic factor, potenti-
ated the UCB-MSCs multipotency and also resulted in
better homing and colonization in liver tissues post-
transplantation [143]. While both native UCB-MSCs
and VEGF165-encoding UCB-MSC restored liver activ-
ity in the ALF rat model, modified stromal cells exhib-
ited more desired therapeutic influences on ALF [143].
Given that IL-35 plays a pivotal role in Treg-induced
immunoregulation, Wang etal. evaluated the therapeu-
tic merits of IL-35 overexpressing MSCs in ALF [144].
ey showed that modified stromal cells migrated
to the damaged tissues and considerably reduced
the necrosis zones of damaged livers. Moreover, IL-
35-MSCs averted hepatocyte apoptosis through down-
regulation of the FASL expression by immune cells.
ey also attenuated IFN-γ levels secreted by immune
cells potently via targeting JAK1-STAT1/STAT4 signal
pathway [144]. As described in previous sections, IL-
1Ra elicits strong anti-inflammatory and antiapoptotic
impacts on immune response in liver failure. Accord-
ingly, Zheng and coworkers showed that transplanta-
tion of IL-1Ra-encoding amniotic fluid (AF)-MSCs by
the portal vein in the ALF rat model led to reduced
mortality as well as ameliorated liver activity [145].
MSCs‑exosome inALF
Exosomes are small membrane-bound EVs that are pro-
duced and then released by numerous types of cells,
such as stem/stromal cells, immune cells, or tumor cells.
Exosomes are comprised of a myriad of biological com-
ponents, including proteins, lipids, mRNAs as well as
miRNAs as cargo, which can be conveyed to the recipi-
ent cells [103]. Such cargo can adjust physiological cell
functions and thereby adapt tissue microenvironment,
and also inspire hepatocyte proliferation, reflecting their
competencies to be described as a rational therapeutic
option in liver diseases, such as ALF (Table3). Reduced
levels of miR-20a-5p accompanied with the enhanced
level of CXCL8, most eminent neutrophil chemoattract-
ants, are mainly observed in hepatocytes during ALF.
But, BM-MSCs-exosome could improve miR-20a-5p
expression and conversely attenuate CXCL8 levels in
hepatocytes [146]. Also, systemic injection of UC-MSC-
exosome (16 mg/kg) induced liver restoration in the
ALF mice model [105]. It was found that glutathione
peroxidase1 (GPX1) enriched exosome-mitigated oxi-
dative stress and apoptosis in the hepatocyte, while the
elimination of GPX1 led to the abrogated UC-MSCs-
exosome-elicited hepatoprotective impacts in mice [105].
In addition, UC-MSC-exosomes potently modified the
membranous expression of CD154 (or CD40 ligand) in
intrahepatic CD4+ T cells, largely contributing to the
inflammatory response in the liver [147]. e suppressive
Table 3 Mesenchymal stromal cells (MSCs) derived molecules (e.g., exosome) in liver failure preclinical models, especially acute liver
failure (ALF)
Silica magnetic graphene oxide (SMGO), NLR family pyrin domain containing 3 (NLRP3), Tumor necrosis factor-ɑ (TNF-ɑ), T helper 1/2 (Th1/2), Vascular endothelial
growth factor (VEGF), Interleukin 8 (IL-8 or CXCL8), Conditioned medium (CM), Embryonic stem cells (ESCs), Glutathione peroxidase1 (GPX1), C-reactive protein (CRP)
Sources Model Intervention Result (ref)
Umbilical cord Mice MSCs-exosome GPX1 enriched exosomes diminished oxidative stress and also apoptosis [105]
Placenta Rat MSCs-exosome CRP enriched exosome provoked angiogenesis by up-regulation of Wnt signaling axis [149]
Bone marrow Rat MSCs-exosome Stimulation of hepatoprotective impacts by exosome-rich fractionated secretome [150]
Bone marrow Mice MSCs-exosome Suppression of NLRP3 in macrophage and thereby reducing ALF by TNF-ɑ pretreated exo-
some [107]
Menstrual blood Mice MSCs-exosome Liver function recovery, improved survival rates, and suppressed hepatocellular apoptosis
[151]
Umbilical cord Mice MSCs-extracellular vesicles Inhibition of T cell activation in liver tissue following reserve of CD154 expression [147]
Bone marrow Mice MSCs-conditioned medium Promoting hepatocyte proliferation, inhibition of their apoptosis, hindrance of the infiltration
of macrophages, improving Th2/Th1 ratio, and enabling hepatic stellate cell (HSC) loss [157]
Bone marrow Rat MSCs-conditioned medium Marked attenuation of panlobular immune cells infiltrates and also hepatocellular apoptosis
[210]
ESCs-MSCs Mice MSCs-conditioned medium Supporting hepatocytes growth by VEGF enriched conditioned medium [156]
Bone marrow Mice MSCs-exosome Attenuation of liver inflammation by exosomal miR-20a-5p/intracellular CXCL8 axis [146]
Bone marrow Rat MSCs-conditioned medium Reduced hepatocyte apoptosis [154]
Bone marrow Rat MSCs-conditioned medium Improving the hepatoprotective impacts of the conditioned medium by SMGO potently
elicited through inhibition of inflammation and loss of hepatocytes [155]
Amniotic fluid Mice MSCs-conditioned medium Hepatic progenitor-like (HPL)-CM showed superiority over amniotic fluid-MSCs in terms of
liver recovery [158]
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 11 of 21
Shokravietal. Stem Cell Research & Therapy (2022) 13:192
effect on CD154 expression and resultant inflamma-
tion was due to the existence of chaperonin containing
TCP1 subunit 2 (CCT2) in these exosomes, which tar-
gets Ca2 + influx and down-regulates CD154 genera-
tion in CD4 + T cells [147]. In another study, Shao etal.
screened the miRNAs in the MSCs-exosomes compli-
cated in inhibition of IL-6-mediated signaling axis in ALF
mice model. ey showed that miR-455-3p was released
by exosomes and efficiently instigated PI3K signaling,
and in turn, sustained hepatocyte proliferation [106].
Also, IL-6 pretreated MSCs or exosomes exhibited higher
levels of miR-455-3p compared with native MSCs or
their derivative exosome. In fact, miR-455-3p-enriched
exosomes suppressed macrophages activation, reduced
local liver injury, and also diminish the expression of pro-
inflammatory cytokines in vivo [106]. e miR-455-3p
also could constrain activation of HSCs and liver fibrosis
upon down-regulation of the heat shock protein (HSP)
47/TGF-β/Smad4 signaling pathway [148]. Importantly,
C-reactive protein (CRP) enriched placenta-derived mes-
enchymal stromal cells (PD-MSCs)- exosome could up-
regulate Wnt signaling pathway as well as angiogenesis
in animal hepatocytes by interacting with endothelial
cells [149]. Another study also revealed that rat BM-
MSCs-exosome-rich fractionated secretome could bring
about a hepatoprotective impact in ALF models mainly
caused by diminished oxidative stress [150]. Similarly,
transplantation of exosomes derived from menstrual
blood-mesenchymal stromal cells (Men-SCs) that con-
tained a diversity of cytokines, such as intercellular adhe-
sion molecule-1 (ICAM-1 or CD54), angiopoietin-2, Axl,
angiogenin, insulin-like growth factor-binding protein
6 (IGFBP-6), osteoprotegerin, IL-6, and IL-8, improved
liver function in the ALF animal model [151]. Treatment
resulted in improved survival rates as well as reserved
hepatocyte apoptosis. Notably, attenuated numbers of
neutrophils and also diminished levels of caspase-3 were
evidenced post-transplantation, assuming that Men-SC-
exosome can be a substitute treatment to support liver
failure [151]. Pretreatment of UC-MSCs-exosome with
TNF-α also enhanced exosome-induced hepatoprotec-
tive influence in the ALF mice model [107]. Pretreated
exosomes led to the attenuated serum ALT, AST, and
pro-inflammatory cytokines levels and concomitantly
down-regulated stimulation of NLRP3 inflammasome.
Molecular analysis revealed that miRNA-299-3p up-reg-
ulated in TNF-α-primed MSCs-exosome played an emi-
nent role in the amelioration of liver damage in ALF by
blocking the NLRP3 pathway [107]. Apart from its role
in liver failure recovery, a miR-299-3p activity as a potent
tumor suppressor has been documented in hepatocellu-
lar carcinoma by alleviating tumor size and venous infil-
tration [152].
MSCs-conditioned medium (CM) could also mod-
ify morphological characteristics of hepatocytes in the
ALF model. Meanwhile, secretome achieved by culti-
vating MSCs with low oxygen content (10%) provoked
more prominent hepatoprotective influence, and sig-
nificantly reduced ALT and AST and also pro-inflamma-
tory cytokines serum levels following injection in vivo
[153]. In another study, Li and coworkers evaluated the
therapeutic merits of CM from MSCs co-cultured with
hepatocytes in the ALF rat model [154]. e apoptotic
cells frequency was lower in CM derived from co-cul-
tured cells than MSCs-CM or hepatocyte-CM. Also, CM
derived from co-cultured cells strikingly alleviated liver
injury and facilitated liver recovery, indicating the advan-
tages of this strategy for liver failure therapy [154]. Also,
silica magnetic graphene oxide (SMGO) could enhance
the hypo protective influences of MSC-CM in ALF
in vivo [155]. Meanwhile, administration of 300 μg/kg
SMGO boosted MSC-CM competencies to avert necro-
sis, apoptosis, and inflammation of hepatocytes. Besides,
SMGO therapy up-regulated the expression of VEGF
and matrix metalloproteinase-9 (MMP-9) invitro [155].
Another report also demonstrated that administration
of CM from embryonic stem cell (ESC)-derived MSCs
potentiated the proliferation of primary hepatocyte and
improved IL-10 secretion from immune cells in vivo
[156]. It appeared that such events might arouse because
of the existence of VEGF in ESC-MSC-CM, which affect
hepatocytes proliferation and migration, generating new
avenues to cure ALF [156]. Likewise, MSC-CM sus-
tained hepatocytes proliferation, reduced their apop-
tosis, compromised macrophages infiltration, elevated
2 and Treg cells population, decreased levels of 17
cells population, and eventually enabled HSCs death in
ALF preclinical model [157]. e MSC-CM injection
caused glycogen synthesis and storage recovery and also
ameliorated ALF with no effect on 1 cells [157]. Also,
CM achieved from either amniotic fluid (AF)-MSCs or
hepatic progenitor-like (HPL) cells derived from AF-
MSCs thanks to the presence of IL-10, IL-1Ra, IL-13, and
IL-27 stimulated liver recovery in the mice model with
ALF [158].
MSCs inliver‑associated conditions (clinical trials)
Several clinical trials have been accomplished or are
ongoing to address the safety, feasibility and efficacy of
MSCs therapy in liver-associated conditions, most fre-
quently in liver failure and liver cirrhosis (Table4, Fig.2).
BM-MSCs and UC-MSCs are most commonly used types
of cells. Of course, there is still no definite standard for
which source of MSCs should be applied for clinical use.
It seems that UC-MSCs are preferred for liver failure
treatment as a result of higher differentiation capability.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 12 of 21
Shokravietal. Stem Cell Research & Therapy (2022) 13:192
Also, the immunogenicity of UC-MSCs is lower than that
of BM-MSCs [159, 160]. Hence, autologous BM-MSCs
and allogeneic UC-MSCs are highly preferred. On the
other hand, poor proliferation, anti-inflammatory and
self-renewal ability impedes AT-MSCs application in
clinic [161]. Although intravenous injection is most used
route, intraportal administration is evidently the optimal
route for MSC therapy in liver-associated conditions due
to the faster engraftment and the prohibited off-target
accumulation. However, we must assess patients’ condi-
tions and the potential risk of applying a particular route
before choosing the administration route.
Liver failure
A study of the safety and preliminary efficacy of UC-MSC
transplantation (3 times at 4-week intervals) was car-
ried out by Ming and colleagues [162]. ey showed that
the intervention had no unwanted effects, while attenu-
ated total bilirubin and ALT levels, prolonged survival
rate, and finally ameliorated liver functions, as evidenced
by improved serum albumin, and prothrombin activity
[162]. As well, intrasplenic and intrahepatic administra-
tion of autologous BM-MSCs derived hepatocyte inspired
short-term amelioration in patient’s ascites, lower limb
edema, and serum albumin [163]. Of course, defining the
life span of the transplanted cells, and also determining
the presence of long-term side effects is urgently required
[163]. Moreover, another trial, which was accomplished
from 2010 to 2013, indicated that systemic administra-
tion of allogeneic BM-MSCs could exert therapeutic
benefits in patients suffering from HBV-related LF [164].
Meanwhile, stromal cell therapy augmented serum total
bilirubin and ultimately promoted the 24-week survival
rate by stimulating liver rescue concomitant with lessen-
ing the occurrences of stern infections compared with the
control group (16.1% versus 33.3%) [164]. Likewise, other
trials also exhibited that autologous BM-MSC transplan-
tation was safe for chronic HBV-induced LF patients, as
Table 4 Clinical trials based on MSCs-based therapies in liver diseases (e.g., ALF)
Gamma-glutamyl transferase (GGT), Alkaline phosphatase (ALP), Bone marrow (BM), Umbilical cord (UC), Umbilical cord blood (UCB), Adipose tissue (AT), Hepatitis C
virus (HCV), Hepatitis B virus (HBV )
Condition Cell Source Participant no Main results (ref )
Primary biliary cirrhosis Allogeneic UC 7 Robust attenuation in serum ALP and GGT levels [168]
Liver failure Allogeneic UC 43 Enchantment in the survival rates without side effects [162]
HBV-induced liver cirrhosis Autologous BM 56 Improving the Treg/Th17 cell ration [171]
Liver cirrhosis Autologous BM 25 Removing the HCV RNA caused by transplanted MSCs-medi-
ated paracrine effect [211]
Decompensated liver cirrhosis Autologous BM 4 Improved the quality of life without serious side effects [167]
Alcoholic liver cirrhosis Autologous BM 12 No side effects in concomitant with histological and quantita-
tive amelioration [212]
HCV-induced liver cirrhosis Autologous BM 40 Normalization of liver enzymes levels in association with resto-
ration in liver function [213]
Liver cirrhosis Autologous BM 8 Improved liver function evidenced by enhanced serum albumin
and reduced total bilirubin[172]
Liver failure Autologous BM-derived hepatocyte 40 Improvement in ascites, lower limb edema as well as serum
albumin levels [163]
Decompensated liver cirrhosis Allogeneic UC 45 Improved level function documented with enhanced serum
albumin levels and reduced total bilirubin levels [180]
HCV-induced liver cirrhosis Autologous BM 20 Amelioration of liver function in Egyptian patients [170]
HCV-induced liver cirrhosis Autologous BM 25 Partial rescue in liver function [169]
Decompensated liver cirrhosis Autologous BM 27 No significant beneficial effect [174]
Liver failure Allogeneic BM 110 Improved overall survival and also reduced incidence of severe
infections [164]
Liver cirrhosis Allogeneic (UC, UCB, BM) 26 Stromal cell injection by peripheral vein was safe and partially
effective [173]
HBV-induced liver cirrhosis Allogeneic UC 40 Enhanced IL-10 levels and also reduced IL-6 and TNF-ɑ levels
[214]
Ischemic-type biliary lesions
following liver transplantation Allogeneic UC 12 Stem cell injection was safe and elicited favorable short-term
outcomes [215]
Alcoholic liver cirrhosis Autologous BM 72 Ameliorated histologic fibrosis and liver normal activity [216]
Liver allograft rejection Allogeneic UC 27 Improved Treg/Th17 cell ratio [217]
Liver allograft rejection Allogeneic BM 10 No side effect [218]
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 13 of 21
Shokravietal. Stem Cell Research & Therapy (2022) 13:192
shown by the incidence of no serious intervention-related
events and carcinoma during 192weeks follow-up [165].
Also, the short-term outcome was promising; however,
long-term efficacy was not clearly amended [165].
Liver cirrhosis
Cirrhosis is a late-stage liver disease in which healthy
liver tissue is substituted with scar tissue and the liver is
perpetually damaged. Liver transplantation is a standard
therapeutic plan aiming to treat liver cirrhosis patients
[166]. Meanwhile, MSCs have recently been noted as a
possible therapeutic option to partially ameliorate liver
function in this condition as a result of their appreciated
antifibrotic and immunoregulatory attributes [55].
A phase 1 trial on 4 patients with decompensated liver
cirrhosis verified the safety and feasibility of MSCs ther-
apy [167]. Moreover, the life quality of all patients was
ameliorated post-transplantation concerning the mean
physical and mental component scales [167]. In primary
biliary cirrhosis patients, UC-MSC injection by periph-
eral vein (3 times at 4-week intervals) exhibited no seri-
ous untoward effects [168]. Also, intervention caused a
Fig. 2 Clinical trials based on mesenchymal stromal cells (MSCs) therapy in liver-associated conditions registered in ClinicalTrials.gov (November
2021). The schematic demonstrates clinical depending on the study phase (A), study status (B), MSCs source (C), study location (D), participant
number (E), and condition (F)
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 14 of 21
Shokravietal. Stem Cell Research & Therapy (2022) 13:192
robust reduction in serum alkaline phosphatase (ALP)
and γ-glutamyltransferase (GGT) levels compared to the
control group during 4years follow-up. Notwithstand-
ing, no alteration was observed in levels of ALT, AST,
total bilirubin, albumin, INR, or the prothrombin time
activity. ereby, comprehensive randomized controlled
cohort trials are justified to authorize the clinical merits
of UC-MSC transplantation [168]. In addition, injection
of autologous BM-MSCs led to a partial amelioration
of liver function in 25 Egyptian patients suffering from
HCV-triggered liver cirrhosis, as evinced by improved
prothrombin activity and serum albumin levels along
with reduced bilirubin level [169]. In a similar condi-
tion, Amin etal. found that intrasplenic administration
of autologous BM-MSCs potentiated liver function with
attenuation in total bilirubin, AST, ALT, prothrombin
time (PT), and also INR levels [170]. Autologous BM-
MSCs therapy also inspired an improvement in liver
function among HBV-related liver cirrhosis patients fol-
lowing transplantation [171]. is trial was conducted in
56 patients with HBV-induced liver cirrhosis, and results
showed an enhancement in Treg/17 ratio post-trans-
plantation during 24-week follow-up [171]. Consistently,
mRNA levels of forkhead box protein P3 (FOXP3), an
eminent Treg-associated transcription factor, strikingly
were diminished, whereas retinoic acid-related orphan
receptor gamma t (RORγt) expression levels which are
tightly in association with 17 cells were reduced. Fur-
ther, the intervention resulted in an enhancement in
TGF-β levels, while IL-17, TNF-α, and IL-6 were signifi-
cantly decreased following transplantation [171]. In con-
trast to several cited trials implying that the autologous
MSC therapy can be a safe and effective alternative for
patients with liver cirrhosis [172, 173], Mohamadnejad
etal. noted that MSC infusion by peripheral vein had no
advantageous result in cirrhotic patients [174]. Overall,
large-scale studies are required to achieve reliable results
concerning MSCs therapy in liver cirrhosis.
Potential risks ofMSC transplantation
e treatment of liver dysfunctions through MSCs has
been the central aim of several clinical and preclini-
cal investigations. In this context, a few issues need to
be dealt with cautiously (e.g., the possible emergence of
carcinogenesis and the transmission of the virus). Dif-
ferent growth factors can be secreted by MSCs, and this
may stimulate the growth of tumor cells and angiogenesis
[175, 176]. e past experimental investigations showed
that the number of passages is a defining factor in ren-
dering a tissue malignant or cancerous. Studies show that
chromosome abnormalities may occur after more than
three passages in the MSCs of mice [177, 178]. Moreover,
MSCs are likely to experience telomeric deletions after
a multitude of passages. Despite the lack of any clini-
cal reports on the malignant transformation of human
MSCs, the follow-up period was not long enough for the
formation of a tumor for most of them [179]. As a result,
there need to be more studies on chromosomal integrity
before MSCs transplantation to make sure that the pro-
cedure is completely safe.
Contrary to autotransplantation, allotransplantation
can pose the danger of the spread of the virus to the
patients [180]. Even though the spread of parvovirus B19
into BM cells was observed invitro, there is no confirmed
case of parvovirus B19-positive MSC-related viremia
in humans. Yet, we do not know the spread of the her-
pes simplex virus (HSV) and cytomegalovirus (CMV)
via MSCs invivo. Owing to these facts, recipients, and
donors of MSC are recommended to be screened for
parvovirus B19, HSV, and CMV, as immunosuppressed
patients are likely to catch infectious [181].
Enhancing thequantity ofMSCs‑secreted
molecules
Now, restricted secretion of soluble mediators, such as
exosome, from parental MSCs fences their wide-ranging
application in clinics. Following some passages, MSCs
mainly demonstrates abrogated competence to produce
and then release soluble factor. Recent studies have indi-
cated that tangential flow filtration (TFF) system-based
tactics support the secretion of greater levels of vesi-
cles from origin stromal cells than vesicle isolation by
ultracentrifuge [182]. Further, ultrasonication of MSC-
derived extracellular vesicles could improve their yields
up to 20-fold [183]. Other proofs are indicating that three
dimensional (3D) culture may facilities the incessant pro-
duction of MSC-derived exosome [184, 185]. Cultivation
of MSCs in 3D cultures together with conventional either
differential ultracentrifugation or TFF also could engen-
der a higher quantity of MSCs-derived secretome [186].
Also, MSCs culture on particular biomaterials, such as
alginate hydrogel [187] and avitene ultrafoam collagen
ease generation of exosome with higher quantity and
also potency [188]. As well, pretreatment of MSCs with
hypoxia or various molecules, in particular cytokines or
chemokines (e.g., IFN-γ, TNFα, IL-1β, IL-6, and TGF-β),
gives largely rise to the secretion of vesicles with greater
regenerative competencies [189–191].
Conclusion andfuture direction
Some investigations in preclinical models of liver dis-
eases, such as ALF, have verified the MSC’s unique com-
petence to establish hepatocyte in vivo. Nonetheless, it
seems that the therapeutic merits of MSCs largely rely
on their aptitudes to secrete a myriad of factors, more
importantly, cytokines, growth factors, and miRNAs,
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 15 of 21
Shokravietal. Stem Cell Research & Therapy (2022) 13:192
facilitating liver recovery. During last two decades, vari-
ous clinical trials have been conducted to evaluate the
capability of MSCs therapy in liver-associated condi-
tions, such as ALF (Table4, Fig. 2); however, achieved
outcomes are quite inconsistent. Given that autologous
MSCs derived from elder patients or patients with obe-
sity experienced abrogated proliferation and differen-
tiation capability, using allogeneic cells in some cased is
urgently required. In this circumstance, screening recip-
ients and donors of MSC for parvovirus B19, HSV, and
CMV are of paramount importance. Taken together, the
providing of a universal MSC quality standard evaluation
system is required.
To determine the mechanism contributed to MSCs
therapy, it is urgently required to determine the pro-
tein, DNA and RNA secreted by MSCs. e proteomics
and transcriptomics can play a pivotal role in evaluating
the underlying mechanism. Notably, improving the fre-
quency of cells homing to the damaged liver is the central
point to potentiate the therapeutic impacts of MSCs. In
fact, investigation of the homing attributes of MSCs is of
paramount importance to augment the effective thera-
peutic quantity of such cells. In published clinical results,
MSCs have been administrated into patients by several
available routes, more frequently intravenous routes fol-
lowed by intrahepatic injection (e.g., by the portal vein
and hepatic artery). Also, intrasplenic injection has been
applied in a few studies. Based on findings, a remarkable
number of cells are trapped in the lungs upon systemic
injection and thereby did not move to the liver afterward.
Hence, finding better administration route is recom-
mended to achieve significant outcome in vivo. Mean-
while, a study indicated that intraportal injection was
more effective than hepatic intra-arterial injection and
also intravenous injection to restore liver injury invivo
[123]. As well, it has been shown that portal vein injec-
tion has superiority over intrasplenic injection [192]. On
the other hand, other reports exhibited that injection by
the hepatic artery was not beneficial for the transdiffer-
entiation of MSCs.
Among the recent clinical trials concerning the MSCs
therapy for liver diseases (e.g., liver failure) treatment,
the total number of MSCs employed was from 106 to
109, irrespective of which method was applied to deliver
the dose. e large range of doses applied is difficult to
explicate as there are few reports including comparisons
of several doses in the same clinical trial. Nonetheless, it
seems that as few as 1 × 107 cells can be helpful based on
recent published results.
In sum, although clinical trials have evidenced the
safety and modest efficacy of short-term application of
MSCs, further trials are warranted before MSCs appli-
cation in clinical to treat ALF and other liver-associated
conditions for optimizing administration routes as well
as dosses.
Abbreviations
MSCs: Mesenchymal stromal cells; ALF: Acute live failure; HGF: Hepatocyte
growth factor; TNF α: Tumor necrosis factor α; IFNγ: Interferon gamma; VEGF:
Vascular endothelial growth factor; BM: Bone marrow; UC: Umbilical cord; AT:
Adipose tissue; miRs: MicroRNAs; TGFβ: Transforming growth factor β; AST:
Aspartate aminotransferase; ALT: Alanine aminotransferase; IL: Interleukin.
Acknowledgements
Not applicable.
Author contributions
All authors contributed to the conception and the main idea of the work. SS,
BAZ, VB, FN, RH, MMK, LT, AS, and SM drafted the main text, figures, and tables.
AZ and SM supervised the work and provided the comments and additional
scientific information. SS and BAZ and AS also reviewed and revised the text.
All authors read and approved the final manuscript.
Funding
No Funders.
Availability of data and materials
Not applicable.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Author details
1 Department of Research and Academic Affairs, Larkin Community Hospital,
Miami, FL, USA. 2 I.M. Sechenov First Moscow State Medical University (Sech-
enov University), Moscow, Russian Federation. 3 Basic Sciences Department,
College of Pharmacy, University of Duhok, Duhok, Kurdistan Region, Iraq.
4 School of Medicine, Abadan University of Medical Sciences, Abadan, Iran.
5 Department of Medicinal Chemistr y, Pharmacy Faculty, Tabriz University
of Medical Sciences, Tabriz, Iran. 6 Department of Oral and Maxillofacial Sur-
gery, School of Dentistry, Shahid Beheshti University of Medical Sciences, Teh-
ran, Iran. 7 Department of Pharmacology, Saveetha Dental College, Saveetha
Institute of Medical and Technical Science, Saveetha University, Chennai, India.
8 Student Research Committee, Tabriz University of Medical Sciences, Tabriz,
Iran. 9 Immunology Research Center, Tabriz University of Medical Sciences,
Tabriz, Iran. 10 Stem Cell Research Center, Tabriz University of Medical Sciences,
Tabriz, Iran.
Received: 19 November 2021 Accepted: 28 February 2022
References
1. Hadem J, Tacke F, Bruns T, Langgartner J, Strnad P, Denk GU, Fikatas P,
Manns MP, Hofmann WP, Gerken G. Etiologies and outcomes of acute
liver failure in Germany. Clin Gastroenterol Hepatol. 2012;10(6):664-9.
e2.
2. Lee WM, editor. Acute liver failure. Seminars in respiratory and critical
care medicine. New York: Thieme Medical Publishers; 2012.
3. Blackmore L, Bernal W. Acute liver failure. Clin Med. 2015;15(5):468.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 16 of 21
Shokravietal. Stem Cell Research & Therapy (2022) 13:192
4. Patton H, Misel M, Gish RG. Acute liver failure in adults: an evidence-
based management protocol for clinicians. Gastroenterol Hepatol.
2012;8(3):161–212.
5. Lee WM. Acute liver failure in the United States. Semin Liver Dis.
2003;23(3):217–26.
6. Tao Y-C, Wang M-L, Chen E-Q, Tang H. Stem cells transplantation in
the treatment of patients with liver failure. Curr Stem Cell Res Ther.
2018;13(3):193–201.
7. Schacher FC, Martins Pezzi da Silva A, Silla LMDR, Álvares-da-Silva MR.
Bone marrow mesenchymal stem cells in acute-on-chronic liver failure
grades 2 and 3: a phase I-II randomized clinical trial. Can J Gastroenterol
Hepatol. 2021;2021:1–9.
8. Choi J, Kang S, Kim B, So S, Han J, Kim G-N, Lee M-Y, Roh S, Lee J-Y, Oh
SJ. Efficient hepatic differentiation and regeneration potential under
xeno-free conditions using mass-producible amnion-derived mesen-
chymal stem cells. Stem Cell Res Ther. 2021;12(1):1–20.
9. Wang J-l, Ding H-r, Pan C-y, Shi X-l, Ren H-z. Mesenchymal stem cells
ameliorate lipid metabolism through reducing mitochondrial damage
of hepatocytes in the treatment of post-hepatectomy liver failure. Cell
Death Dis. 2021;12(1):1–15.
10. Marofi F, Vahedi G, Hasanzadeh A, Salarinasab S, Arzhanga P, Khademi B,
Farshdousti HM. Mesenchymal stem cells as the game-changing tools
in the treatment of various organs disorders: Mirage or reality? J Cell
Physiol. 2019;234(2):1268–88.
11. Saito Y, Ikemoto T, Morine Y, Shimada M. Current status of hepatocyte-
like cell therapy from stem cells. Surg Today. 2021;51(3):340–9.
12. Markov A, Thangavelu L, Aravindhan S, Zekiy AO, Jarahian M, Chartrand
MS, Pathak Y, Marofi F, Shamlou S, Hassanzadeh A. Mesenchymal stem/
stromal cells as a valuable source for the treatment of immune-medi-
ated disorders. Stem Cell Res Ther. 2021;12(1):1–30.
13. Tavakoli S, Ghaderi Jafarbeigloo HR, Shariati A, Jahangiryan A, Jadidi F,
Jadidi Kouhbanani MA, Hassanzadeh A, Zamani M, Javidi K, Naimi A.
Mesenchymal stromal cells; a new horizon in regenerative medicine. J
Cell Physiol. 2020;235(12):9185–210.
14. Moghadasi S, Elveny M, Rahman HS, Suksatan W, Jalil AT, Abdelbasset
WK, Yumashev AV, Shariatzadeh S, Motavalli R, Behzad F, et al. A para-
digm shift in cell-free approach: the emerging role of MSCs-derived
exosomes in regenerative medicine. J Transl Med. 2021;19(1):302.
15. Hassanzadeh A, Rahman HS, Markov A, Endjun JJ, Zekiy AO, Chartrand
MS, Beheshtkhoo N, Kouhbanani MAJ, Marofi F, Nikoo M. Mesenchymal
stem/stromal cell-derived exosomes in regenerative medicine and
cancer; overview of development, challenges, and opportunities. Stem
Cell Res Ther. 2021;12(1):1–22.
16. Golchin A, Hosseinzadeh S, Ardeshirylajimi A. The exosomes released
from different cell types and their effects in wound healing. J Cell
Biochem. 2018;119(7):5043–52.
17. Marote A, Teixeira FG, Mendes-Pinheiro B, Salgado AJ. MSCs-derived
exosomes: cell-secreted nanovesicles with regenerative potential. Front
Pharmacol. 2016;7:231.
18. Jadli AS, Ballasy N, Edalat P, Patel VB. Inside (sight) of tiny communica-
tor: exosome biogenesis, secretion, and uptake. Mol Cell Biochem.
2020;467(1):77–94.
19. Nakamura Y, Kita S, Tanaka Y, Fukuda S, Obata Y, Okita T, Nishida H, Taka-
hashi Y, K awachi Y, Tsugawa-Shimizu Y. Adiponectin stimulates exosome
release to enhance mesenchymal stem-cell-driven therapy of heart
failure in mice. Mol Ther. 2020;28(10):2203–19.
20. Psaraki A, Ntari L, Karakostas C, Korrou-Karava D, Roubelakis MG.
Extracellular vesicles derived from mesenchymal stem/stromal cells: the
regenerative impact in liver diseases. Hepatology. 2021;14:261–8.
21. Simmons OL, Meinzer C, Rule J, Lee WM. Liver transplantation for aceta-
minophen-induced acute liver failure: role of psychiatric comorbidity in
listing decisions and outcomes. Dig Dis Sci. 2020;65(6):1861–8.
22. Ostapowicz G, Fontana RJ, Schiødt FV, Larson A, Davern TJ, Han SH,
McCashland TM, Shakil AO, Hay JE, Hynan L, et al. Results of a prospec-
tive study of acute liver failure at 17 tertiary care centers in the United
States. Ann Intern Med. 2002;137(12):947–54.
23. Dong V, Nanchal R, Karvellas CJ. Pathophysiology of acute liver failure.
Nutr Clin Pract. 2020;35(1):24–9.
24. Riordan SM, Williams R. Acute liver failure: targeted artificial and hepat-
ocyte-based support of liver regeneration and reversal of multiorgan
failure. J Hepatol. 2000;32:63–76.
25. Chapel A, Bertho JM, Bensidhoum M, Fouillard L, Young RG, Frick J,
Demarquay C, Cuvelier F, Mathieu E, Trompier F. Mesenchymal stem
cells home to injured tissues when co-infused with hematopoietic cells
to treat a radiation-induced multi-organ failure syndrome. J Gene Med.
2003;5(12):1028–38.
26. Bone RC. Sepsis, the sepsis syndrome, multi-organ failure: a plea for
comparable definitions. Philadelphia: American College of Physicians;
1991.
27. Das J, Ghosh J, Manna P, Sil PC. Acetaminophen induced acute liver
failure via oxidative stress and JNK activation: protective role of
taurine by the suppression of cytochrome P450 2E1. Free Radic Res.
2010;44(3):340–55.
28. Jiang W-P, Deng J-S, Huang S-S, Wu S-H, Chen C-C, Liao J-C, Chen H-Y,
Lin H-Y, Huang G-J. Sanghuangporus sanghuang mycelium prevents
paracetamol-induced hepatotoxicity through regulating the MAPK/
NF-κB, Keap1/Nrf2/HO-1, TLR4/PI3K/Akt, and CaMKKβ/LKB1/AMPK
pathways and suppressing oxidative stress and inflammation. Antioxi-
dants. 2021;10(6):897.
29. Shi S, Wang L, van der Laan LJ, Pan Q, Verstegen MM. Mitochon-
drial dysfunction and oxidative stress in liver transplantation and
underlying diseases: new insights and therapeutics. Transplantation.
2021;105(11):2362–73.
30. Wu X, Dong L, Lin X, Li J. Relevance of the NLRP3 inflammasome in the
pathogenesis of chronic liver disease. Front Immunol. 2017;8:1728.
31. Del Campo JA, Gallego P, Grande L. Role of inflammatory response in
liver diseases: therapeutic strategies. World J Hepatol. 2018;10(1):1.
32. He K, Zhu X, Liu Y, Miao C, Wang T, Li P, Zhao L, Chen Y, Gong J, Cai C.
Inhibition of NLRP3 inflammasome by thioredoxin-interacting protein
in mouse Kupffer cells as a regulatory mechanism for non-alcoholic
fatty liver disease development. Oncotarget. 2017;8(23):37657.
33. Zhan C, Lin G, Huang Y, Wang Z, Zeng F, Wu S. A dopamine-precursor-
based nanoprodrug for in-situ drug release and treatment of acute
liver failure by inhibiting NLRP3 inflammasome and facilitating liver
regeneration. Biomaterials. 2021;268:120573.
34. Woolbright BL, Jaeschke H. Role of the inflammasome in aceta-
minophen-induced liver injury and acute liver failure. J Hepatol.
2017;66(4):836–48.
35. Zhao Q, Wu C-S, Fang Y, Qian Y, Wang H, Fan Y-C, Wang K. Glucocorti-
coid regulates NLRP3 in acute-on-chronic hepatitis B liver failure. Int J
Med Sci. 2019;16(3):461.
36. Tao Y, Wang N, Qiu T, Sun X. The role of autophagy and NLRP3 inflam-
masome in liver fibrosis. BioMed Res Int. 2020;2020:1–8.
37. Li L, Shan S, Kang K, Zhang C, Kou R, Song F. The cross-talk of NLRP3
inflammasome activation and necroptotic hepatocyte death in
acetaminophen-induced mice acute liver injury. Hum Exp Toxicol.
2021;40(4):673–84.
38. Choi J, Kang S, Kim B, So S, Han J, Kim G-N, Lee M-Y, Roh S, Lee J-Y, Oh
SJ, et al. Efficient hepatic differentiation and regeneration potential
under xeno-free conditions using mass-producible amnion-derived
mesenchymal stem cells. Stem Cell Res Ther. 2021;12(1):569.
39. Zhang S, Yang Y, Fan L, Zhang F, Li L. The clinical application of mesen-
chymal stem cells in liver disease: the current situation and potential
future. Ann Transl Med. 2020;8(8):565.
40. Du XX, Shi Y, Yang Y, Yu Y, Lou HG, Lv FF, Chen Z, Yang Q. DAMP molecu-
lar IL-33 augments monocytic inflammatory storm in hepatitis B-precip-
itated acute-on-chronic liver failure. Liver Int. 2018;38(2):229–38.
41. Li M, Ling T, Teng F, Hu C, Su Z, Zhang C, Li X, Zhao T, Mu X, Li Y. CD5L
deficiency attenuate acetaminophen-induced liver damage in mice
via regulation of JNK and ERK signaling pathway. Cell Death Discov.
2021;7(1):1–11.
42. Weiss ARR, Dahlke MH. Immunomodulation by mesenchymal stem
cells (MSCs): mechanisms of action of living, apoptotic, and dead MSCs.
Front Immunol. 2019;10:1191.
43. Song N, Scholtemeijer M, Shah K. Mesenchymal stem cell immu-
nomodulation: mechanisms and therapeutic potential. Trends Pharma-
col Sci. 2020;41:653–64.
44. Carreras-Planella L, Monguió-Tortajada M, Borràs FE, Franquesa M.
Immunomodulatory effect of MSC on B cells is independent of
secreted extracellular vesicles. Front Immunol. 2019;10:1288.
45. Sun S-J, Lai W-H, Jiang Y, Zhen Z, Wei R, Lian Q, Liao S-Y, Tse H-F.
Immunomodulation by systemic administration of human-induced
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 17 of 21
Shokravietal. Stem Cell Research & Therapy (2022) 13:192
pluripotent stem cell-derived mesenchymal stromal cells to enhance
the therapeutic efficacy of cell-based therapy for treatment of myocar-
dial infarction. Theranostics. 2021;11(4):1641.
46. Bahroudi M, Bakhshi B, Soudi S, Najar-Peerayeh S. Immunomodulatory
effects of mesenchymal stem cell-conditioned media on lipopolysac-
charide of Vibrio cholerae as a vaccine candidate. Stem Cell Res Ther.
2021;12(1):1–14.
47. Putra A, Ridwan FB, Putridewi AI, Kustiyah AR, Wirastuti K, Sadyah NAC,
Rosdiana I, Munir D. The role of TNF-α induced MSCs on suppressive
inflammation by increasing TGF-β and IL-10. Open Access Maced J Med
Sci. 2018;6(10):1779.
48. Wang L, Deng Z, Sun Y, Zhao Y, Li Y, Yang M, Yuan R, Liu Y, Qian Z, Zhou
F. The study on the regulation of Th cells by MSCs through the JAK-STAT
signaling pathway to protect naturally aged sepsis model rats. Front
Immunol. 2021;13:820685. https:// doi. org/ 10. 3389/ fimmu. 2022. 820685.
49. Akiyama K, Chen C, Wang D, Xu X, Qu C, Yamaza T, Cai T, Chen W,
Sun L, Shi S. Mesenchymal-stem-cell-induced immunoregulation
involves FAS-ligand-/FAS-mediated T cell apoptosis. Cell Stem Cell.
2012;10(5):544–55.
50. Miloradovic D, Miloradovic D, Markovic BS, Acovic A, Harrell CR, Djonov
V, Arsenijevic N, Volarevic V. The effects of mesenchymal stem cells on
antimelanoma immunity depend on the timing of their administration.
Stem Cells Int. 2020;2020:1–13.
51. Volarevic V, Nurkovic J, Arsenijevic N, Stojkovic M. Concise review: thera-
peutic potential of mesenchymal stem cells for the treatment of acute
liver failure and cirrhosis. Stem Cells. 2014;32(11):2818–23.
52. Bataller R, Brenner DA. Liver fibrosis. J Clin Investig. 2005;115(2):209–18.
53. Hu C, Wu Z, Li L. Mesenchymal stromal cells promote liver regeneration
through regulation of immune cells. Int J Biol Sci. 2020;16(5):893.
54. Huang B, Cheng X, Wang H, Huang W, Wang D, Zhang K, Zhang H, Xue
Z, Da Y, Zhang N. Mesenchymal stem cells and their secreted molecules
predominantly ameliorate fulminant hepatic failure and chronic liver
fibrosis in mice respectively. J Transl Med. 2016;14(1):1–12.
55. Tsuchiya A, Takeuchi S, Watanabe T, Yoshida T, Nojiri S, Ogawa M, Terai S.
Mesenchymal stem cell therapies for liver cirrhosis: MSCs as “conduct-
ing cells” for improvement of liver fibrosis and regeneration. Inflamm
Regen. 2019;39(1):1–6.
56. Friedenstein A, Piatetzky-Shapiro I, Petrakova K. Osteogenesis in trans-
plants of bone marrow cells. Development. 1966;16(3):381–90.
57. Friedenstein AJ, Deriglasova UF, Kulagina NN, Panasuk AF, Rudakowa SF,
Luriá EA, Ruadkow IA. Precursors for fibroblasts in different populations
of hematopoietic cells as detected by the in vitro colony assay method.
Exp Hematol. 1974;2(2):83–92.
58. Ullah I, Seo K, Wi H, Kim Y, Lee S, Ock SA. Induction of the differentia-
tion of porcine bone marrow mesenchymal stem cells into premature
hepatocyte-like cells in an indirect coculture system with primary
hepatocytes. Anim Cells Syst. 2020;24(5):289–98.
59. Ji R, Zhang N, You N, Li Q, Liu W, Jiang N, Liu J, Zhang H, Wang D, Tao
K. The differentiation of MSCs into functional hepatocyte-like cells in a
liver biomatrix scaffold and their transplantation into liver-fibrotic mice.
Biomaterials. 2012;33(35):8995–9008.
60. Afshari A, Shamdani S, Uzan G, Naserian S, Azarpira N. Different
approaches for transformation of mesenchymal stem cells into
hepatocyte-like cells. Stem Cell Res Ther. 2020;11(1):1–14.
61. Afshari A, Shamdani S, Uzan G, Naserian S, Azarpira N. Different
approaches for transformation of mesenchymal stem cells into
hepatocyte-like cells. Stem Cell Res Ther. 2020;11(1):54.
62. Taléns-Visconti R, Bonora A, Jover R, Mirabet V, Carbonell F, Castell JV,
Gómez-Lechón MJ. Hepatogenic differentiation of human mesenchy-
mal stem cells from adipose tissue in comparison with bone marrow
mesenchymal stem cells. World J Gastroenterol: WJG. 2006;12(36):5834.
63. Ye JS, Su XS, Stoltz JF, de Isla N, Zhang L. Signalling pathways involved
in the process of mesenchymal stem cells differentiating into hepato-
cytes. Cell Prolif. 2015;48(2):157–65.
64. Popovici C, Roubin R, Coulier F, Birnbaum D. An evolutionary history of
the FGF superfamily. BioEssays. 2005;27(8):849–57.
65. Battula VL, Bareiss PM, Treml S, Conrad S, Albert I, Hojak S, Abele H,
Schewe B, Just L, Skutella T. Human placenta and bone marrow derived
MSC cultured in serum-free, b-FGF-containing medium express cell
surface frizzled-9 and SSEA-4 and give rise to multilineage differentia-
tion. Differentiation. 2007;75(4):279–91.
66. Eom YW, Oh J-E, Lee JI, Baik SK, Rhee K-J, Shin HC, Kim YM, Ahn
CM, Kong JH, Kim HS. The role of growth factors in maintenance of
stemness in bone marrow-derived mesenchymal stem cells. Biochem
Biophys Res Commun. 2014;445(1):16–22.
67. Wang Y, Yu X, Chen E, Li L. Liver-derived human mesenchymal stem
cells: a novel therapeutic source for liver diseases. Stem Cell Res Ther.
2016;7(1):1–8.
68. Neuss S, Becher E, Wöltje M, Tietze L, Jahnen-Dechent W. Functional
expression of HGF and HGF receptor/c-met in adult human mesen-
chymal stem cells suggests a role in cell mobilization, tissue repair, and
wound healing. Stem Cells. 2004;22(3):405–14.
69. Park B-W, Jung S-H, Das S, Lee SM, Park J-H, Kim H, Hwang J-W, Lee
S, Kim H-J, Kim H-Y. In vivo priming of human mesenchymal stem
cells with hepatocyte growth factor–engineered mesenchymal
stem cells promotes therapeutic potential for cardiac repair. Sci Adv.
2020;6(13):eaay6994.
70. Forte G, Minieri M, Cossa P, Antenucci D, Sala M, Gnocchi V, Fiaccavento
R, Carotenuto F, De Vito P, Baldini PM. Hepatocyte growth factor effects
on mesenchymal stem cells: proliferation, migration, and differentia-
tion. Stem Cells. 2006;24(1):23–33.
71. Chivu M, Dima SO, Stancu CI, Dobrea C, Uscatescu V, Necula LG, Bleotu
C, Tanase C, Albulescu R, Ardeleanu C. In vitro hepatic differentiation
of human bone marrow mesenchymal stem cells under differential
exposure to liver-specific factors. Transl Res. 2009;154(3):122–32.
72. Dai LJ, Li HY, Guan LX, Ritchie G, Zhou JX. The therapeutic potential of
bone marrow-derived mesenchymal stem cells on hepatic cirrhosis.
Stem Cell Res. 2009;2(1):16–25.
73. Yan Y, Xu W, Qian H, Si Y, Zhu W, Cao H, Zhou H, Mao F. Mesenchymal
stem cells from human umbilical cords ameliorate mouse hepatic
injury in vivo. Liver Int. 2009;29(3):356–65.
74. Zhang GZ, Sun HC, Zheng LB, Guo JB, Zhang XL. In vivo hepatic dif-
ferentiation potential of human umbilical cord-derived mesenchymal
stem cells: Therapeutic effect on liver fibrosis/cirrhosis. World J Gastro-
enterol. 2017;23(46):8152–68.
75. Tsiapalis D, O’Driscoll L. Mesenchymal stem cell derived extracellular
vesicles for tissue engineering and regenerative medicine applications.
Cells. 2020;9(4):991.
76. Chen L, Zhang C, Chen L, Wang X, Xiang B, Wu X, Guo Y, Mou X, Yuan
L, Chen B, et al. Human menstrual blood-derived stem cells ameliorate
liver fibrosis in mice by targeting hepatic stellate cells via paracrine
mediators. Stem Cells Transl Med. 2017;6(1):272–84.
77. Choi JS, Jeong IS, Han JH, Cheon SH, Kim S-W. IL-10-secreting
human MSCs generated by TALEN gene editing ameliorate liver
fibrosis through enhanced anti-fibrotic activity. Biomater Sci.
2019;7(3):1078–87.
78. Xuan J, Feng W, An Z, Yang J, Xu H, Li J, Zhao Z, Wen W. Anti-tgf [beta]-1
receptor inhibitor mediates the efficacy of the human umbilical cord
mesenchymal stem cells against liver fibrosis through tgf [beta]-1/smad
pathway. Mol Cell Biochem. 2017;429(1–2):113.
79. Jang YO, Cho M-Y, Yun C-O, Baik SK, Park K-S, Cha S-K, Chang SJ, Kim MY,
Lim YL, Kwon SO. Effect of function-enhanced mesenchymal stem cells
infected with decorin-expressing adenovirus on hepatic fibrosis. Stem
Cells Transl Med. 2016;5(9):1247–56.
80. Pietrosi G, Fernández-Iglesias A, Pampalone M, Ortega-Ribera M, Lozano
JJ, García-Calderó H, Abad-Jordà L, Conaldi PG, Parolini O, Vizzini G.
Human amniotic stem cells improve hepatic microvascular dysfunction
and portal hypertension in cirrhotic rats. Liver Int. 2020;40(10):2500–14.
81. Kim M-D, Kim S-S, Cha H-Y, Jang S-H, Chang D-Y, Kim W, Suh-Kim H,
Lee J-H. Therapeutic effect of hepatocyte growth factor-secreting
mesenchymal stem cells in a rat model of liver fibrosis. Exp Mol Med.
2014;46(8):e110.
82. Rockel JS, Rabani R, Viswanathan S, editors. Anti-fibrotic mechanisms of
exogenously-expanded mesenchymal stromal cells for fibrotic diseases.
Semin Cell Dev Biol. 2020;101:87–103.
83. Motawi TM, Atta HM, Sadik NA, Azzam M. The therapeutic effects of
bone marrow-derived mesenchymal stem cells and simvastatin in a rat
model of liver fibrosis. Cell Biochem Biophys. 2014;68(1):111–25.
84. Raafat N, Aal SMA, Abdo FK, El Ghonaimy NM. Mesenchymal stem
cells: in vivo therapeutic application ameliorates carbon tetrachloride
induced liver fibrosis in rats. Int J Biochem Cell Biol. 2015;68:109–18.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 18 of 21
Shokravietal. Stem Cell Research & Therapy (2022) 13:192
85. Wang J, Bian C, Liao L, Zhu Y, Li J, Zeng L, Zhao RC. Inhibition of
hepatic stellate cells proliferation by mesenchymal stem cells and
the possible mechanisms. Hepatol Res. 2009;39(12):1219–28.
86. An SY, Jang YJ, Lim H-J, Han J, Lee J, Lee G, Park JY, Park S-Y, Kim JH,
Do B-R. Milk fat globule-EGF factor 8, secreted by mesenchymal
stem cells, protects against liver fibrosis in mice. Gastroenterology.
2017;152(5):1174–86.
87. Chen S, Lin N, Pan W, Hu K, Xu R. Activation of Notch1 signaling
by marrow-derived mesenchymal stem cells through cell–cell
contact inhibits proliferation of hepatic stellate cells. Life Sci.
2011;89(25–26):975–81.
88. Lee C, Kim M, Han J, Yoon M, Jung Y. Mesenchymal stem cells influ-
ence activation of hepatic stellate cells, and constitute a promising
therapy for liver fibrosis. Biomedicines. 2021;9(11):1598.
89. Duman DG, Zibandeh N, Ugurlu MU, Celikel C, Akkoc T, Banzragch
M, Genc D, Ozdogan O, Akkoc T. Mesenchymal stem cells suppress
hepatic fibrosis accompanied by expanded intrahepatic natural killer
cells in rat fibrosis model. Mol Biol Rep. 2019;46(3):2997–3008.
90. De Maria N, Colantonl A, Fagiuoli S, Liu G-J, Rogers BK, Farinati F, Van
Thiel DH, Floyd RA. Association between reactive oxygen species
and disease activity in chronic hepatitis C. Free Radic Biol Med.
1996;21(3):291–5.
91. Takemoto K, Hatano E, Iwaisako K, Takeiri M, Noma N, Ohmae S,
Toriguchi K, Tanabe K, Tanaka H, Seo S. Necrostatin-1 protects against
reactive oxygen species (ROS)-induced hepatotoxicity in acetami-
nophen-induced acute liver failure. FEBS Open Bio. 2014;4:777–87.
92. Choe G, Kim S-W, Park J, Park J, Kim S, Kim YS, Ahn Y, Jung D-W, Wil-
liams DR, Lee JY. Anti-oxidant activity reinforced reduced graphene
oxide/alginate microgels: mesenchymal stem cell encapsulation and
regeneration of infarcted hearts. Biomaterials. 2019;225:119513.
93. Dey R, Kemp K, Gray E, Rice C, Scolding N, Wilkins A. Human mes-
enchymal stem cells increase anti-oxidant defences in cells derived
from patients with Friedreich’s ataxia. Cerebellum. 2012;11(4):861–71.
94. Murakami T, Nagamura Y, Hirano K. The recovering effect of betaine
on carbon tetrachloride-induced liver injury. J Nutr Sci Vitaminol.
1998;44(2):249–55.
95. Mitsuhashi M, Morimura K, Wanibuchi H, Kiyota A, Wada S, Nakatani
T, Fukushima S. Examination of the rat model of liver injury via
thioacetamide (TAA) or carbon tetrachloride (CCl4). J Toxicol Pathol.
2004;17(3):219–22.
96. Eom YW, Shim KY, Baik SK. Mesenchymal stem cell therapy for liver
fibrosis. Korean J Intern Med. 2015;30(5):580.
97. Raafat N, Abdel Aal SM, Abdo FK, El Ghonaimy NM. Mesenchymal
stem cells: in vivo therapeutic application ameliorates carbon
tetrachloride induced liver fibrosis in rats. Int J Biochem Cell Biol.
2015;68:109–18.
98. Cho KA, Woo SY, Seoh JY, Han HS, Ryu KH. Mesenchymal stem cells
restore CCl4-induced liver injury by an antioxidative process. Cell Biol
Int. 2012;36(12):1267–74.
99. Quintanilha LF, Takami T, Hirose Y, Fujisawa K, Murata Y, Yamamoto N,
Goldenberg RC, Terai S, Sakaida I. Canine mesenchymal stem cells
show antioxidant properties against thioacetamide-induced liver injury
in vitro and in vivo. Hepatol Res. 2014;44(10):E206–17.
100. Phinney DG, Pittenger MF. Concise review: msc-derived exosomes for
cell-free therapy. Stem Cells. 2017;35(4):851–8.
101. Razeghian E, Margiana R, Chupradit S, Bokov DO, Abdelbasset WK,
Marofi F, Shariatzadeh S, Tosan F, Jarahian M. Mesenchymal stem/stro-
mal cells as a vehicle for cytokine delivery: an emerging approach for
tumor immunotherapy. Front Med. 2021;8:721174.
102. Rahbaran M, Baghini SS, Mardasi M, Razeghian E. MSCs modifies the
proliferation of leukemia MOLT-4 cells and induces their apoptosis
through up-regulating Bax, caspase-3, and-8, and down-regulating
Bcl-2 expression. Ann Cancer Res Ther. 2021;29(1):79–84.
103. Zhang S, Hou Y, Yang J, Xie D, Jiang L, Hu H, Hu J, Luo C, Zhang Q. Appli-
cation of mesenchymal stem cell exosomes and their drug-loading
systems in acute liver failure. J Cell Mol Med. 2020;24(13):7082–93.
104. Jiang L, Zhang S, Hu H, Yang J, Wang X, Ma Y, Jiang J, Wang J, Zhong L,
Chen M. Exosomes derived from human umbilical cord mesenchymal
stem cells alleviate acute liver failure by reducing the activity of the
NLRP3 inflammasome in macrophages. Biochem Biophys Res Com-
mun. 2019;508(3):735–41.
105. Yan Y, Jiang W, Tan Y, Zou S, Zhang H, Mao F, Gong A, Qian H, Xu W.
hucMSC exosome-derived GPX1 is required for the recovery of hepatic
oxidant injury. Mol Ther. 2017;25(2):465–79.
106. Shao M, Xu Q, Wu Z, Chen Y, Shu Y, Cao X, Chen M, Zhang B, Zhou Y, Yao
R. Exosomes derived from human umbilical cord mesenchymal stem
cells ameliorate IL-6-induced acute liver injury through miR-455-3p.
Stem Cell Res Ther. 2020;11(1):1–13.
107. Zhang S, Jiang L, Hu H, Wang H, Wang X, Jiang J, Ma Y, Yang J, Hou Y, Xie
D, et al. Pretreatment of exosomes derived from hUCMSCs with TNF-α
ameliorates acute liver failure by inhibiting the activation of NLRP3 in
macrophage. Life Sci. 2020;246:117401.
108. Hao NB, Li CZ, Lü MH, Tang B, Wang SM, Wu YY, Liang GP, Yang SM.
SDF-1/CXCR4 axis promotes MSCs to repair liver injury partially through
trans-differentiation and fusion with hepatocytes. Stem Cells Int.
2015;2015:960387.
109. Zhang S, Zhu Z, Wang Y, Liu S, Zhao C, Guan W, Zhao Y. Therapeutic
potential of Bama miniature pig adipose stem cells induced hepato-
cytes in a mouse model with acute liver failure. Cytotechnology.
2018;70(4):1131–41.
110. Wang J, Ren H, Yuan X, Ma H, Shi X, Ding Y. Interleukin-10 secreted by
mesenchymal stem cells attenuates acute liver failure through inhibit-
ing pyroptosis. Hepatol Res. 2018;48(3):E194-e202.
111. Wu X, Dong L, Lin X, Li J. Relevance of the NLRP3 inflammasome in the
pathogenesis of chronic liver disease. Front Immunol. 2017;8:1728.
112. Ma HC, Wang X, Wu MN, Zhao X, Yuan XW, Shi XL. Interleukin-10 con-
tributes to therapeutic effect of mesenchymal stem cells for acute liver
failure via signal transducer and activator of transcription 3 signaling
pathway. Chin Med J (Engl). 2016;129(8):967–75.
113. Liu Y, Ren H, Wang J, Yang F, Li J, Zhou Y, Yuan X, Zhu W, Shi X. Pros-
taglandin E(2) secreted by mesenchymal stem cells protects against
acute liver failure via enhancing hepatocyte proliferation. FASEB J.
2019;33(2):2514–25.
114. Zhou JH, Lu X, Yan CL, Sheng XY, Cao HC. Mesenchymal stromal cell-
dependent immunoregulation in chemically-induced acute liver failure.
World J Stem Cells. 2021;13(3):208–20.
115. Liu L, Song H, Duan H, Chai J, Yang J, Li X, Yu Y, Zhang X, Hu X, Xiao M,
et al. TSG-6 secreted by human umbilical cord-MSCs attenuates severe
burn-induced excessive inflammation via inhibiting activations of P38
and JNK signaling. Sci Rep. 2016;6(1):30121.
116. Wang Y, Wang JL, Ma HC, Tang ZT, Ding HR, Shi XL. Mesenchymal stem
cells increase heme oxygenase 1-activated autophagy in treatment of
acute liver failure. Biochem Biophys Res Commun. 2019;508(3):682–9.
117. Zhang ZH, Zhu W, Ren HZ, Zhao X, Wang S, Ma HC, Shi XL. Mesenchy-
mal stem cells increase expression of heme oxygenase-1 leading to
anti-inflammatory activity in treatment of acute liver failure. Stem Cell
Res Ther. 2017;8(1):70.
118. Zhao X, Shi XL, Zhang ZH, Ma HC, Yuan XW, Ding YT. Role of neutrophils
in treatment of rats with D-galactosamine-induced acute liver failure
with bone marrow mesenchymal stem cells. Zhonghua Gan Zang Bing
Za Zhi. 2016;24(8):601–7.
119. Guo G, Zhuang X, Xu Q, Wu Z, Zhu Y, Zhou Y, Li Y, Lu Y, Zhang B, Talbot P,
et al. Peripheral infusion of human umbilical cord mesenchymal stem
cells rescues acute liver failure lethality in monkeys. Stem Cell Res Ther.
2019;10(1):84.
120. Zhang Y, Li Y, Li W, Cai J, Yue M, Jiang L, Xu R, Zhang L, Li J, Zhu C.
Therapeutic effect of human umbilical cord mesenchymal stem
cells at various passages on acute liver failure in rats. Stem Cells Int.
2018;2018:7159465.
121. He Y, Guo X, Lan T, Xia J, Wang J, Li B, Peng C, Chen Y, Hu X, Meng Z.
Human umbilical cord-derived mesenchymal stem cells improve
the function of liver in rats with acute-on-chronic liver failure via
downregulating Notch and Stat1/Stat3 signaling. Stem Cell Res Ther.
2021;12(1):396.
122. Ding HR, Wang JL, Tang ZT, Wang Y, Zhou G, Liu Y, Ren HZ, Shi XL.
Mesenchymal stem cells improve glycometabolism and liver regenera-
tion in the treatment of post-hepatectomy liver failure. Front Physiol.
2019;10:412.
123. Sang JF, Shi XL, Han B, Huang T, Huang X, Ren HZ, Ding YT. Intraportal
mesenchymal stem cell transplantation prevents acute liver failure
through promoting cell proliferation and inhibiting apoptosis. Hepato-
biliary Pancreat Dis Int. 2016;15(6):602–11.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 19 of 21
Shokravietal. Stem Cell Research & Therapy (2022) 13:192
124. Putra A, Rosdiana I, Darlan DM, Alif I, Hayuningtyas F, Wijaya I, Aryanti R,
Makarim FR, Antari AD. Intravenous administration is the best route of
mesenchymal stem cells migration in improving liver function enzyme
of acute liver failure. Folia Med (Plovdiv). 2020;62(1):52–8.
125. Zare H, Jamshidi S, Dehghan MM, Saheli M, Piryaei A. Bone marrow or
adipose tissue mesenchymal stem cells: comparison of the thera-
peutic potentials in mice model of acute liver failure. J Cell Biochem.
2018;119(7):5834–42.
126. Ali M, Payne SL. Biomaterial-based cell delivery strategies to promote
liver regeneration. Biomater Res. 2021;25(1):5.
127. Liu M, Yang J, Hu W, Zhang S, Wang Y. Superior performance of co-
cultured mesenchymal stem cells and hepatocytes in poly(lactic acid-
glycolic acid) scaffolds for the treatment of acute liver failure. Biomed
Mater. 2016;11(1):015008.
128. Kang HT, Jun DW, Jang K, Hoh JK, Lee JS, Saeed WK, Chae YJ, Lee JH.
Effect of stem cell treatment on acute liver failure model using scaffold.
Dig Dis Sci. 2019;64(3):781–91.
129. Ghaedi M, Soleimani M, Shabani I, Duan Y, Lotfi AS. Hepatic differentia-
tion from human mesenchymal stem cells on a novel nanofiber scaf-
fold. Cell Mol Biol Lett. 2012;17(1):89–106.
130. Xu L, Wang S, Sui X, Wang Y, Su Y, Huang L, Zhang Y, Chen Z, Chen Q,
Du H, et al. Mesenchymal stem cell-seeded regenerated silk fibroin
complex matrices for liver regeneration in an animal model of acute
liver failure. ACS Appl Mater Interfaces. 2017;9(17):14716–23.
131. Wang L, Li S, Wang HY, Zeng J, Zhang ZZ, Lv DY, Kuang WH. In a rat
model of acute liver failure, Icaritin improved the therapeutic effect
of mesenchymal stem cells by activation of the hepatocyte growth
factor/c-met pathway. Evid Based Complement Alternat Med.
2019;2019:4253846.
132. Chen H, Tang S, Liao J, Liu M, Lin Y. Therapeutic effect of human
umbilical cord blood mesenchymal stem cells combined with G-CSF
on rats with acute liver failure. Biochem Biophys Res Commun.
2019;517(4):670–6.
133. Chavez-Tapia NC, Mendiola-Pastrana I, Ornelas-Arroyo VJ, Noreña-
Herrera C, Vidaña-Perez D, Delgado-Sanchez G, Uribe M, Barrientos-
Gutierrez T. Granulocyte-colony stimulating factor for acute-on-chronic
liver failure: systematic review and meta-analysis. Ann Hepatol.
2015;14(5):631–41.
134. Nam HH, Jun DW, Jang K, Saeed WK, Lee JS, Kang HT, Chae YJ.
Granulocyte colony stimulating factor treatment in non-alcoholic
fatty liver disease: beyond marrow cell mobilization. Oncotarget.
2017;8(58):97965–76.
135. Sang JF, Shi XL, Han B, Huang X, Huang T, Ren HZ, Ding YT. Combined
mesenchymal stem cell transplantation and interleukin-1 recep-
tor antagonism after partial hepatectomy. World J Gastroenterol.
2016;22(16):4120–35.
136. Xiao JQ, Shi XL, Tan JJ, Zhang L, Xu Q, Ding YT. A novel treatment regi-
men for acute liver failure based on a combination of mesenchymal
stem cells transplantation and IL-lRa-loaded chitosan nanoparticles.
Zhonghua Gan Zang Bing Za Zhi. 2013;21(4):308–14.
137. Nasiri E, Alizadeh A, Roushandeh AM, Gazor R, Hashemi-Firouzi N,
Golipoor Z. Melatonin-pretreated adipose-derived mesenchymal stem
cells efficeintly improved learning, memory, and cognition in an animal
model of Alzheimer’s disease. Metab Brain Dis. 2019;34(4):1131–43.
138. Huang P, Wang L, Li Q, Tian X, Xu J, Xu J, Xiong Y, Chen G, Qian H, Jin C,
et al. Atorvastatin enhances the therapeutic efficacy of mesenchymal
stem cells-derived exosomes in acute myocardial infarction via up-reg-
ulating long non-coding RNA H19. Cardiovasc Res. 2020;116(2):353–67.
139. Nie H, An F, Mei J, Yang C, Zhan Q, Zhang Q. IL-1β Pretreatment
improves the efficacy of mesenchymal stem cells on acute liver failure
by enhancing CXCR4 expression. Stem Cells Int. 2020;2020:1498315.
140. Mohsin S, Shams S, Ali Nasir G, Khan M, Javaid Awan S, Khan SN, Riazud-
din S. Enhanced hepatic differentiation of mesenchymal stem cells after
pretreatment with injured liver tissue. Differentiation. 2011;81(1):42–8.
141. Li QY, Chen J, Luo YH, Zhang W, Xiao EH. Sodium Butyrate Pre-Treat-
ment Enhance Differentiation of Bone Marrow Mesenchymal Stem
Cells (BM-MSCs) into Hepatocytes and Improve Liver Injury. Curr Mol
Med. 2021;1.
142. Ma HC, Shi XL, Ren HZ, Yuan XW, Ding YT. Targeted migration of mesen-
chymal stem cells modified with CXCR4 to acute failing liver improves
liver regeneration. World J Gastroenterol. 2014;20(40):14884–94.
143. Chen H, Tang S, Liao J, Liu M, Lin Y. VEGF(165) gene-modified human
umbilical cord blood mesenchymal stem cells protect against acute
liver failure in rats. J Gene Med. 2021;23(10):e3369.
144. Wang W, Guo H, Li H, Yan Y, Wu C, Wang X, He X, Zhao N. Interleu-
kin-35 gene-modified mesenchymal stem cells protect concanavalin
A-induced fulminant hepatitis by decreasing the interferon gamma
level. Hum Gene Ther. 2018;29(2):234–41.
145. Zheng YB, Zhang XH, Huang ZL, Lin CS, Lai J, Gu YR, Lin BL, Xie DY, Xie
SB, Peng L, et al. Amniotic-fluid-derived mesenchymal stem cells over-
expressing interleukin-1 receptor antagonist improve fulminant hepatic
failure. PLoS ONE. 2012;7(7):e41392.
146. Zhang J, Gao J, Lin D, Xiong J, Wang J, Chen J, Lin B, Gao Z. Potential
networks regulated by MSCs in acute-on-chronic liver failure: exosomal
miRNAs and intracellular target genes. Front Genet. 2021;12:650536.
147. Zheng J, Lu T, Zhou C, Cai J, Zhang X, Liang J, Sui X, Chen X, Chen L,
Sun Y, et al. Extracellular vesicles derived from human umbilical cord
mesenchymal stem cells protect liver ischemia/reperfusion injury by
reducing CD154 expression on CD4+ T cells via CCT2. Adv Sci (Weinh).
2020;7(18):1903746.
148. Wei S, Wang Q, Zhou H, Qiu J, Li C, Shi C, Zhou S, Liu R, Lu L. miR-455-3p
alleviates hepatic stellate cell activation and liver fibrosis by suppress-
ing HSF1 expression. Mol Ther Nucleic Acids. 2019;16:758–69.
149. Jun JH, Kim JY, Choi JH, Lim JY, Kim K, Kim GJ. Exosomes from placenta-
derived mesenchymal stem cells are involved in liver regenera-
tion in hepatic failure induced by bile duct ligation. Stem Cells Int.
2020;2020:5485738.
150. Damania A, Jaiman D, Teotia AK, Kumar A. Mesenchymal stromal cell-
derived exosome-rich fractionated secretome confers a hepatoprotec-
tive effect in liver injury. Stem Cell Res Ther. 2018;9(1):31.
151. Chen L, Xiang B, Wang X, Xiang C. Exosomes derived from human
menstrual blood-derived stem cells alleviate fulminant hepatic failure.
Stem Cell Res Ther. 2017;8(1):9.
152. Dang S, Zhou J, Wang Z, Wang K, Dai S, He S. MiR-299-3p functions as
a tumor suppressor via targeting Sirtuin 5 in hepatocellular carcinoma.
Biomed Pharmacother. 2018;106:966–75.
153. Temnov A, Rogov K, Zhalimov V, Igor P, Pekov S, Bader A, Sklifas A,
Giri S. The effect of a mesenchymal stem cell conditioned medium
fraction on morphological characteristics of hepatocytes in acetami-
nophen-induced acute liver failure: a preliminary study. Hepat Med.
2019;11:89–96.
154. Chen L, Zhang J, Yang L, Zhang G, Wang Y, Zhang S. The effects of
conditioned medium derived from mesenchymal stem cells cocultured
with hepatocytes on damaged hepatocytes and acute liver failure in
rats. Stem Cells Int. 2018;2018:9156560.
155. Foroutan T, Kabiri F, Motamedi E. Silica magnetic graphene oxide
improves the effects of stem cell-conditioned medium on acute liver
failure. ACS Omega. 2021;6(33):21194–206.
156. Lotfinia M, Kadivar M, Piryaei A, Pournasr B, Sardari S, Sodeifi N,
Sayahpour FA, Baharvand H. Effect of secreted molecules of human
embryonic stem cell-derived mesenchymal stem cells on acute hepatic
failure model. Stem Cells Dev. 2016;25(24):1898–908.
157. Huang B, Cheng X, Wang H, Huang W, la Ga HuZ, Wang D, Zhang K,
Zhang H, Xue Z, Da Y, et al. Mesenchymal stem cells and their secreted
molecules predominantly ameliorate fulminant hepatic failure and
chronic liver fibrosis in mice respectively. J Transl Med. 2016;14:45.
158. Zagoura DS, Roubelakis MG, Bitsika V, Trohatou O, Pappa KI, Kapelou-
zou A, Antsaklis A, Anagnou NP. Therapeutic potential of a distinct
population of human amniotic fluid mesenchymal stem cells and
their secreted molecules in mice with acute hepatic failure. Gut.
2012;61(6):894–906.
159. Cho PS, Messina DJ, Hirsh EL, Chi N, Goldman SN, Lo DP, Harris IR,
Popma SH, Sachs DH, Huang CA. Immunogenicity of umbilical cord
tissue–derived cells. Blood. 2008;111(1):430–8.
160. Deuse T, Stubbendorff M, Tang-Quan K, Phillips N, Kay MA, Eiermann T,
Phan TT, Volk H-D, Reichenspurner H, Robbins RC. Immunogenicity and
immunomodulatory properties of umbilical cord lining mesenchymal
stem cells. Cell Transplant. 2011;20(5):655–67.
161. Strioga M, Viswanathan S, Darinskas A, Slaby O, Michalek J. Same or
not the same? Comparison of adipose tissue-derived versus bone
marrow-derived mesenchymal stem and stromal cells. Stem Cells Dev.
2012;21(14):2724–52.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 20 of 21
Shokravietal. Stem Cell Research & Therapy (2022) 13:192
162. Shi M, Zhang Z, Xu R, Lin H, Fu J, Zou Z, Zhang A, Shi J, Chen L, Lv S,
et al. Human mesenchymal stem cell transfusion is safe and improves
liver function in acute-on-chronic liver failure patients. Stem Cells Transl
Med. 2012;1(10):725–31.
163. Amer ME, El-Sayed SZ, El-Kheir WA, Gabr H, Gomaa AA, El-Noomani N,
Hegazy M. Clinical and laboratory evaluation of patients with end-stage
liver cell failure injected with bone marrow-derived hepatocyte-like
cells. Eur J Gastroenterol Hepatol. 2011;23(10):936–41.
164. Lin BL, Chen JF, Qiu WH, Wang KW, Xie DY, Chen XY, Liu QL, Peng L,
Li JG, Mei YY, et al. Allogeneic bone marrow-derived mesenchymal
stromal cells for hepatitis B virus-related acute-on-chronic liver failure: a
randomized controlled trial. Hepatology. 2017;66(1):209–19.
165. Peng L, Xie DY, Lin BL, Liu J, Zhu HP, Xie C, Zheng YB, Gao ZL. Autolo-
gous bone marrow mesenchymal stem cell transplantation in liver fail-
ure patients caused by hepatitis B: short-term and long-term outcomes.
Hepatology. 2011;54(3):820–8.
166. Tsochatzis EA, Bosch J, Burroughs AK. Liver cirrhosis. Lancet.
2014;383(9930):1749–61.
167. Mohamadnejad M, Alimoghaddam K, Mohyeddin-Bonab M, Bagheri
M, Bashtar M, Ghanaati H, Baharvand H, Ghavamzadeh A, Malekzadeh
R. Phase 1 trial of autologous bone marrow mesenchymal stem cell
transplantation in patients with decompensated liver cirrhosis. Arch
Iran Med. 2007;10(4):459–66.
168. Wang L, Li J, Liu H, Li Y, Fu J, Sun Y, Xu R, Lin H, Wang S, Lv S, et al. Pilot
study of umbilical cord-derived mesenchymal stem cell transfusion
in patients with primary biliary cirrhosis. J Gastroenterol Hepatol.
2013;28(Suppl 1):85–92.
169. El-Ansary M, Abdel-Aziz I, Mogawer S, Abdel-Hamid S, Hammam O,
Teaema S, Wahdan M. Phase II trial: undifferentiated versus dif-
ferentiated autologous mesenchymal stem cells transplantation in
Egyptian patients with HCV induced liver cirrhosis. Stem Cell Rev Rep.
2012;8(3):972–81.
170. Amin MA, Sabry D, Rashed LA, Aref WM, el-Ghobary MA, Farhan MS,
Fouad HA, Youssef YA. Short-term evaluation of autologous transplanta-
tion of bone marrow-derived mesenchymal stem cells in patients with
cirrhosis: Egyptian study. Clin Transplant. 2013;27(4):607–12.
171. Xu L, Gong Y, Wang B, Shi K, Hou Y, Wang L, Lin Z, Han Y, Lu L, Chen D,
et al. Randomized trial of autologous bone marrow mesenchymal stem
cells transplantation for hepatitis B virus cirrhosis: regulation of Treg/
Th17 cells. J Gastroenterol Hepatol. 2014;29(8):1620–8.
172. Kharaziha P, Hellström PM, Noorinayer B, Farzaneh F, Aghajani K, Jafari
F, Telkabadi M, Atashi A, Honardoost M, Zali MR, et al. Improvement of
liver function in liver cirrhosis patients after autologous mesenchymal
stem cell injection: a phase I-II clinical trial. Eur J Gastroenterol Hepatol.
2009;21(10):1199–205.
173. Liang J, Zhang H, Zhao C, Wang D, Ma X, Zhao S, Wang S, Niu L, Sun
L. Effects of allogeneic mesenchymal stem cell transplantation in
the treatment of liver cirrhosis caused by autoimmune diseases. Int J
Rheum Dis. 2017;20(9):1219–26.
174. Mohamadnejad M, Alimoghaddam K, Bagheri M, Ashrafi M, Abdol-
lahzadeh L, Akhlaghpoor S, Bashtar M, Ghavamzadeh A, Malekzadeh R.
Randomized placebo-controlled trial of mesenchymal stem cell trans-
plantation in decompensated cirrhosis. Liver Int. 2013;33(10):1490–6.
175. Ball SG, Shuttleworth CA, Kielty CM. Mesenchymal stem cells and neo-
vascularization: role of platelet-derived growth factor receptors. J Cell
Mol Med. 2007;11(5):1012–30.
176. Kim DH, Yoo KH, Choi KS, Choi J, Choi S-Y, Yang S-E, Yang Y-S, Im HJ, Kim
KH, Jung HL. Gene expression profile of cytokine and growth factor
during differentiation of bone marrow-derived mesenchymal stem cell.
Cytokine. 2005;31(2):119–26.
177. Zhou YF, Bosch-Marce M, Okuyama H, Krishnamachary B, Kimura
H, Zhang L, Huso DL, Semenza GL. Spontaneous transformation of
cultured mouse bone marrow-derived stromal cells. Cancer Res.
2006;66(22):10849–54.
178. Røsland GV, Svendsen A, Torsvik A, Sobala E, McCormack E, Immervoll
H, Mysliwietz J, Tonn JC, Goldbrunner R, Lønning PE, et al. Long-term
cultures of bone marrow-derived human mesenchymal stem cells
frequently undergo spontaneous malignant transformation. Cancer
Res. 2009;69(13):5331–9.
179. Dahl J-A, Duggal S, Coulston N, Millar D, Melki J, Shahdadfar A, Brinch-
mann JE, Collas P. Genetic and epigenetic instability of human bone
marrow mesenchymal stem cells expanded in autologous serum or
fetal bovine serum. Int J Dev Biol. 2002;52(8):1033–42.
180. Zhang Z, Lin H, Shi M, Xu R, Fu J, Lv J, Chen L, Lv S, Li Y, Yu S, et al.
Human umbilical cord mesenchymal stem cells improve liver function
and ascites in decompensated liver cirrhosis patients. J Gastroenterol
Hepatol. 2012;27(Suppl 2):112–20.
181. Kang SH, Kim MY, Eom YW, Baik SK. Mesenchymal stem cells for
the treatment of liver disease: present and perspectives. Gut Liver.
2020;14(3):306–15.
182. Kim JY, Rhim W-K, Yoo Y-I, Kim D-S, Ko K-W, Heo Y, Park CG, Han DK.
Defined MSC exosome with high yield and purity to improve regenera-
tive activity. J Tissue Eng. 2021;12:20417314211008624.
183. Wang L, Abhange KK, Wen Y, Chen Y, Xue F, Wang G, Tong J, Zhu C, He
X, Wan Y. Preparation of engineered extracellular vesicles derived from
human umbilical cord mesenchymal stem cells with ultrasonication for
skin rejuvenation. ACS Omega. 2019;4(27):22638–45.
184. Cao J, Wang B, Tang T, Lv L, Ding Z, Li Z, Hu R, Wei Q, Shen A, Fu Y. Three-
dimensional culture of MSCs produces exosomes with improved yield
and enhanced therapeutic efficacy for cisplatin-induced acute kidney
injury. Stem Cell Res Ther. 2020;11(1):1–13.
185. Yan L, Wu X. Exosomes produced from 3D cultures of umbilical cord
mesenchymal stem cells in a hollow-fiber bioreactor show improved
osteochondral regeneration activity. Cell Biol Toxicol. 2020;36(2):165–78.
186. Haraszti RA, Miller R, Stoppato M, Sere YY, Coles A, Didiot M-C, Wollacott
R, Sapp E, Dubuke ML, Li X. Exosomes produced from 3D cultures of
MSCs by tangential flow filtration show higher yield and improved
activity. Mol Ther. 2018;26(12):2838–47.
187. Qazi TH, Mooney DJ, Duda GN, Geissler S. Biomaterials that promote
cell-cell interactions enhance the paracrine function of MSCs. Biomate-
rials. 2017;140:103–14.
188. Phan J, Kumar P, Hao D, Gao K, Farmer D, Wang A. Engineering mes-
enchymal stem cells to improve their exosome efficacy and yield for
cell-free therapy. J Extracell Vesicles. 2018;7(1):1522236.
189. Lee B-C, Kang K-S. Functional enhancement strategies for immu-
nomodulation of mesenchymal stem cells and their therapeutic
application. Stem Cell Res Ther. 2020;11(1):1–10.
190. Cunningham CJ, Redondo-Castro E, Allan SM. The therapeutic potential
of the mesenchymal stem cell secretome in ischaemic stroke. J Cereb
Blood Flow Metab. 2018;38(8):1276–92.
191. Nakao Y, Fukuda T, Zhang Q, Sanui T, Shinjo T, Kou X, Chen C, Liu D,
Watanabe Y, Hayashi C. Exosomes from TNF-α-treated human gingiva-
derived MSCs enhance M2 macrophage polarization and inhibit peri-
odontal bone loss. Acta Biomater. 2021;122:306–24.
192. Amer M-EM, El-Sayed SZ, Abou El-Kheir W, Gabr H, Gomaa AA, El-
Noomani N, Hegazy M. Clinical and laboratory evaluation of patients
with end-stage liver cell failure injected with bone marrow-derived
hepatocyte-like cells. Eur J Gastroenterol Hepatol. 2011;23(10):936–41.
193. Saleh M, Taher M, Sohrabpour AA, Vaezi AA, Nasiri Toosi M, Kavianpour
M, Ghazvinian Z, Abdolahi S, Verdi J. Perspective of placenta derived
mesenchymal stem cells in acute liver failure. Cell Biosci. 2020;10:71.
194. Tautenhahn HM, Brückner S, Baumann S, Winkler S, Otto W, von Bergen
M, Bartels M, Christ B. Attenuation of postoperative acute liver failure by
mesenchymal stem cell treatment due to metabolic implications. Ann
Surg. 2016;263(3):546–56.
195. Gilsanz C, Aller MA, Fuentes-Julian S, Prieto I, Blázquez-Martinez A,
Argudo S, Fernández-Delgado J, Beleña J, Arias J, De Miguel MP.
Adipose-derived mesenchymal stem cells slow disease progression of
acute-on-chronic liver failure. Biomed Pharmacother. 2017;91:776–87.
196. Lin NC, Wu HH, Ho JH, Liu CS, Lee OK. Mesenchymal stem cells prolong
survival and prevent lethal complications in a porcine model of fulmi-
nant liver failure. Xenotransplantation. 2019;26(6):e12542.
197. Wang J-L, Ding H-R, Pan C-Y, Shi X-L, Ren H-Z. Mesenchymal stem cells
ameliorate lipid metabolism through reducing mitochondrial damage
of hepatocytes in the treatment of post-hepatectomy liver failure. Cell
Death Dis. 2021;12(1):111.
198. Amiri F, Molaei S, Bahadori M, Nasiri F, Deyhim MR, Jalili MA, Nourani
MR, Habibi RM. Autophagy-modulated human bone marrow-derived
mesenchymal stem cells accelerate liver restoration in mouse models
of acute liver failure. Iran Biomed J. 2016;20(3):135–44.
199. Hao N-B, Li C-Z, Lü M-H, Tang B, Wang S-M, Wu Y-Y, Liang G-P, Yang S-M.
SDF-1/CXCR4 axis promotes MSCs to repair liver injury partially through
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 21 of 21
Shokravietal. Stem Cell Research & Therapy (2022) 13:192
•
fast, convenient online submission
•
thorough peer review by experienced researchers in your field
•
rapid publication on acceptance
•
support for research data, including large and complex data types
•
gold Open Access which fosters wider collaboration and increased citations
maximum visibility for your research: over 100M website views per year
•
At BMC, research is always in progress.
Learn more biomedcentral.com/submissions
Ready to submit your research
Ready to submit your research
? Choose BMC and benefit from:
? Choose BMC and benefit from:
trans-differentiation and fusion with hepatocytes. Stem Cells Int.
2015;2015:960387.
200. Ramanathan R, Rupert S, Selvaraj S, Satyanesan J, Vennila R, Rajagopal
S. Role of human Wharton’s Jelly derived mesenchymal stem cells (WJ-
MSCs) for rescue of d-galactosamine induced acute liver injury in mice.
J Clin Exp Hepatol. 2017;7(3):205–14.
201. Huang YJ, Chen P, Lee CY, Yang SY, Lin MT, Lee HS, Wu YM. Protec-
tion against acetaminophen-induced acute liver failure by omentum
adipose tissue derived stem cells through the mediation of Nrf2 and
cytochrome P450 expression. J Biomed Sci. 2016;23:5.
202. Zhang S, Chen L, Liu T, Zhang B, Xiang D, Wang Z, Wang Y. Human
umbilical cord matrix stem cells efficiently rescue acute liver failure
through paracrine effects rather than hepatic differentiation. Tissue Eng
Part A. 2012;18(13–14):1352–64.
203. Liao H, Du S, Jiang T, Zheng M, Xiang Z, Yang J. UMSCs attenuate
LPS/D-GalN-induced acute liver failure in mice by down-regulating the
MyD88/NF-κB pathway. J Clin Transl Hepatol. 2021;9(5):690–701.
204. Milosavljevic N, Gazdic M, Simovic Markovic B, Arsenijevic A, Nurkovic
J, Dolicanin Z, Djonov V, Lukic ML, Volarevic V. Mesenchymal stem
cells attenuate acute liver injury by altering ratio between interleu-
kin 17 producing and regulatory natural killer T cells. Liver Transpl.
2017;23(8):1040–50.
205. Fathy M, Okabe M, Saad Eldien HM, Yoshida T. AT-MSCs antifibrotic
activity is improved by eugenol through modulation of TGF-β/Smad
signaling pathway in rats. Molecules. 2020;25(2):348.
206. Zhao X, Shi X, Zhang Z, Ma H, Yuan X, Ding Y. Combined treatment with
MSC transplantation and neutrophil depletion ameliorates D-GalN/
LPS-induced acute liver failure in rats. Clin Res Hepatol Gastroenterol.
2016;40(6):730–8.
207. Kong D, Xu H, Chen M, Yu Y, Qian Y, Qin T, Tong Y, Xia Q, Hang H. Co-
encapsulation of HNF4α overexpressing UMSCs and human primary
hepatocytes ameliorates mouse acute liver failure. Stem Cell Res Ther.
2020;11(1):449.
208. Feng J, Yao W, Zhang Y, Xiang AP, Yuan D, Hei Z. Intravenous anesthet-
ics enhance the ability of human bone marrow-derived mesenchymal
stem cells to alleviate hepatic ischemia-reperfusion injury in a receptor-
dependent manner. Cell Physiol Biochem. 2018;47(2):556–66.
209. Despeyroux A, Duret C, Gondeau C, Perez-Gracia E, Chuttoo L, de
Boussac H, Briolotti P, Bony C, Noël D, Jorgensen C, et al. Mesenchymal
stem cells seeded on a human amniotic membrane improve liver
regeneration and mouse survival after extended hepatectomy. J Tissue
Eng Regen Med. 2018;12(4):1062–73.
210. Parekkadan B, van Poll D, Suganuma K, Carter EA, Berthiaume F, Tilles
AW, Yarmush ML. Mesenchymal stem cell-derived molecules reverse
fulminant hepatic failure. PLoS ONE. 2007;2(9):e941.
211. Kantarcıoğlu M, Demirci H, Avcu F, Karslıoğlu Y, Babayiğit MA, Karaman
B, Öztürk K, Gürel H, Akdoğan Kayhan M, Kaçar S, et al. Efficacy of
autologous mesenchymal stem cell transplantation in patients with
liver cirrhosis. Turk J Gastroenterol. 2015;26(3):244–50.
212. Jang YO, Kim YJ, Baik SK, Kim MY, Eom Y W, Cho MY, Park HJ, Park SY,
Kim BR, Kim JW, et al. Histological improvement following administra-
tion of autologous bone marrow-derived mesenchymal stem cells for
alcoholic cirrhosis: a pilot study. Liver Int. 2014;34(1):33–41.
213. Salama H, Zekri AR, Medhat E, Al Alim SA, Ahmed OS, Bahnassy AA,
Lotfy MM, Ahmed R, Musa S. Peripheral vein infusion of autologous
mesenchymal stem cells in Egyptian HCV-positive patients with end-
stage liver disease. Stem Cell Res Ther. 2014;5(3):70.
214. Fang X, Liu L, Dong J, Zhang J, Song H, Song Y, Huang Y, Cui X, Lin J,
Chen C, et al. A study about immunomodulatory effect and efficacy
and prognosis of human umbilical cord mesenchymal stem cells in
patients with chronic hepatitis B-induced decompensated liver cirrho-
sis. J Gastroenterol Hepatol. 2018;33(4):774–80.
215. Zhang YC, Liu W, Fu BS, Wang GY, Li HB, Yi HM, Jiang N, Wang G, Zhang
J, Yi SH, et al. Therapeutic potentials of umbilical cord-derived mesen-
chymal stromal cells for ischemic-type biliary lesions following liver
transplantation. Cytotherapy. 2017;19(2):194–9.
216. Suk KT, Yoon JH, Kim MY, Kim CW, Kim JK, Park H, Hwang SG, Kim DJ,
Lee BS, Lee SH, et al. Transplantation with autologous bone marrow-
derived mesenchymal stem cells for alcoholic cirrhosis: phase 2 trial.
Hepatology. 2016;64(6):2185–97.
217. Shi M, Liu Z, Wang Y, Xu R, Sun Y, Zhang M, Yu X, Wang H, Meng L, Su
H, et al. A pilot study of mesenchymal stem cell therapy for acute liver
allograft rejection. Stem Cells Transl Med. 2017;6(12):2053–61.
218. Detry O, Vandermeulen M, Delbouille MH, Somja J, Bletard N, Briquet
A, Lechanteur C, Giet O, Baudoux E, Hannon M, et al. Infusion of mes-
enchymal stromal cells after deceased liver transplantation: a phase I-II,
open-label, clinical study. J Hepatol. 2017;67(1):47–55.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in pub-
lished maps and institutional affiliations.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
1.
2.
3.
4.
5.
6.
Terms and Conditions
Springer Nature journal content, brought to you courtesy of Springer Nature Customer Service Center GmbH (“Springer Nature”).
Springer Nature supports a reasonable amount of sharing of research papers by authors, subscribers and authorised users (“Users”), for small-
scale personal, non-commercial use provided that all copyright, trade and service marks and other proprietary notices are maintained. By
accessing, sharing, receiving or otherwise using the Springer Nature journal content you agree to these terms of use (“Terms”). For these
purposes, Springer Nature considers academic use (by researchers and students) to be non-commercial.
These Terms are supplementary and will apply in addition to any applicable website terms and conditions, a relevant site licence or a personal
subscription. These Terms will prevail over any conflict or ambiguity with regards to the relevant terms, a site licence or a personal subscription
(to the extent of the conflict or ambiguity only). For Creative Commons-licensed articles, the terms of the Creative Commons license used will
apply.
We collect and use personal data to provide access to the Springer Nature journal content. We may also use these personal data internally within
ResearchGate and Springer Nature and as agreed share it, in an anonymised way, for purposes of tracking, analysis and reporting. We will not
otherwise disclose your personal data outside the ResearchGate or the Springer Nature group of companies unless we have your permission as
detailed in the Privacy Policy.
While Users may use the Springer Nature journal content for small scale, personal non-commercial use, it is important to note that Users may
not:
use such content for the purpose of providing other users with access on a regular or large scale basis or as a means to circumvent access
control;
use such content where to do so would be considered a criminal or statutory offence in any jurisdiction, or gives rise to civil liability, or is
otherwise unlawful;
falsely or misleadingly imply or suggest endorsement, approval , sponsorship, or association unless explicitly agreed to by Springer Nature in
writing;
use bots or other automated methods to access the content or redirect messages
override any security feature or exclusionary protocol; or
share the content in order to create substitute for Springer Nature products or services or a systematic database of Springer Nature journal
content.
In line with the restriction against commercial use, Springer Nature does not permit the creation of a product or service that creates revenue,
royalties, rent or income from our content or its inclusion as part of a paid for service or for other commercial gain. Springer Nature journal
content cannot be used for inter-library loans and librarians may not upload Springer Nature journal content on a large scale into their, or any
other, institutional repository.
These terms of use are reviewed regularly and may be amended at any time. Springer Nature is not obligated to publish any information or
content on this website and may remove it or features or functionality at our sole discretion, at any time with or without notice. Springer Nature
may revoke this licence to you at any time and remove access to any copies of the Springer Nature journal content which have been saved.
To the fullest extent permitted by law, Springer Nature makes no warranties, representations or guarantees to Users, either express or implied
with respect to the Springer nature journal content and all parties disclaim and waive any implied warranties or warranties imposed by law,
including merchantability or fitness for any particular purpose.
Please note that these rights do not automatically extend to content, data or other material published by Springer Nature that may be licensed
from third parties.
If you would like to use or distribute our Springer Nature journal content to a wider audience or on a regular basis or in any other manner not
expressly permitted by these Terms, please contact Springer Nature at
onlineservice@springernature.com
Content uploaded by Raheleh Hazrati
Author content
All content in this area was uploaded by Raheleh Hazrati on Jun 08, 2022
Content may be subject to copyright.
Content uploaded by Raheleh Hazrati
Author content
All content in this area was uploaded by Raheleh Hazrati on May 10, 2022
Content may be subject to copyright.
