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Liver structure and hepatic fibrogenic cells. The liver consists of lobules, representing the hepatic functional unit (panel A). Each lobule is intersected by a central vein (CV), from which hepatocyte cords radiate towards portal triads (PT) containing three different structures: bile ducts (BD), hepatic artery (HA) and portal vein (PV). Hepatocyte cords are separated by sinusoids, blood vessels lined by specialized fenestrated endothelial cells (liver sinusoidal cells). Hepatic stellate cells (HSC) are located in the space of Disse, and portal fibroblasts (PF) in the portal triad areas. Under injury conditions, both HSC and PF can be activated to myofibroblasts (ECM-producing cells). Ductular epithelial cells, another cell type involved during liver injury, line the bile ducts.
Source publication
Myofibroblasts are key fibrogenic cells responsible for excessive extracellular matrix synthesis characterizing the fibrotic lesion. In liver fibrosis, myofibroblasts derive either from activation of hepatic stellate cells (HSC) and portal fibroblasts (PF), or from the activation of fibroblasts that originate from ductular epithelial cells undergoi...
Contexts in source publication
Context 1
... fibrogenic hepatic cells. Among these, myofibroblasts are the key cells responsible for the excessive extra- cellular matrix (ECM) synthesis characterizing the fibrotic lesion, and their increased number correlates with the severity of liver fibrosis [2]. Myofibroblasts derive from the activation of resident mesenchymal populations: HSC and PF ( Fig. 1), or from epithelial (ductular epithelial cells) or endothelial (liver sinusoidal endothelial cells: LSEC) resident cells that directly or indirectly contribute to myofibroblast generation (Fig. ...
Context 2
... number correlates with the severity of liver fibrosis [2]. Myofibroblasts derive from the activation of resident mesenchymal populations: HSC and PF ( Fig. 1), or from epithelial (ductular epithelial cells) or endothelial (liver sinusoidal endothelial cells: LSEC) resident cells that directly or indirectly contribute to myofibroblast generation (Fig. ...
Context 3
... growing experimental evidence has shown that duc- tular epithelial cells ( Fig. 1) also contribute to biliary fibrosis [9]. In the early stage of biliary liver injury, ductular epithelial cells give rise to a composite reaction named 'ductular reaction' characterized by a marked expansion of the ductular compartment which adopts an inflammatory phenotype. Reactive ductular epithelial cells can undergo ...
Context 4
... LSEC ( Fig. 1) represent another liver cell population with a role in the fibrogenic process [13]. These cells are specific endothelial cells which, containing fenestrae and lacking the basement mem- brane, allow an efficient exchange of metabolites and oxygen between the blood and hepatocytes. Under normal conditions, they produce paracrine factors ...
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Liver fibrosis is an excessive and imbalanced deposition of fibrous extracellular matrix (ECM) that is associated with the hepatic wound-healing response. It is also the common mechanism that contributes to the impairment of the liver function that is observed in many chronic liver diseases (CLD). Despite the efforts, no effective therapy against f...
Background & aims:
Hepatic sinusoidal cells are known actors in the fibrogenic response to injury. Activated hepatic stellate cells (HSCs), liver sinusoidal endothelial cells, and Kupffer cells are responsible for sinusoidal capillarization and perisinusoidal matrix deposition impairing vascular exchange and heightening the risk of advanced fibros...
Liver fibrosis is mediated by myofibroblasts, a specialized cell type involved in wound healing and extracellular matrix production. Hepatic stellate cells (HSC) are the major source of myofibroblasts in the fibrotic livers. In the present study we investigated the involvement of CXXC-type zinc-finger protein 5 (CXXC5) in HSC activation and the und...
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Citations
... In the space of Disse, hepatic stellate cells are situated, while portal fibroblasts are located in the portal triad regions. Under conditions of injury, both hepatic stellate cells and portal fibroblasts can undergo activation, transforming into myofibroblasts, responsible for the production of extracellular matrix (ECM) [23]. ECM, synthesized by activated hepatic stellate cells and portal fibroblasts, provides structural support to the liver. ...
Background
Effective communication is crucial for broad acceptance and applicability of alternative methods in 3R biomedical research and preclinical testing. 3D bioprinting is used to construct intricate biological structures towards functional liver models, specifically engineered for deployment as alternative models in drug screening, toxicological investigations, and tissue engineering. Despite a growing number of reviews in this emerging field, a comprehensive study, systematically assessing practices and reporting quality for bioprinted liver models is missing.
Methods
In this systematic scoping review we systematically searched MEDLINE (Ovid), EMBASE (Ovid) and BioRxiv for studies published prior to June 2nd, 2022. We extracted data on methodological conduct, applied bioinks, the composition of the printed model, performed experiments and model applications. Records were screened for eligibility and data were extracted from included articles by two independent reviewers from a panel of seven domain experts specializing in bioprinting and liver biology. We used RAYYAN for the screening process and SyRF for data extraction. We used R for data analysis, and R and Graphpad PRISM for visualization.
Results
Through our systematic database search we identified 1042 records, from which 63 met the eligibility criteria for inclusion in this systematic scoping review. Our findings revealed that extrusion-based printing, in conjunction with bioinks composed of natural components, emerged as the predominant printing technique in the bioprinting of liver models. Notably, the HepG2 hepatoma cell line was the most frequently employed liver cell type, despite acknowledged limitations. Furthermore, 51% of the printed models featured co-cultures with non-parenchymal cells to enhance their complexity. The included studies offered a variety of techniques for characterizing these liver models, with their primary application predominantly focused on toxicity testing. Among the frequently analyzed liver markers, albumin and urea stood out. Additionally, Cytochrome P450 (CYP) isoforms, primarily CYP3A and CYP1A, were assessed, and select studies employed nuclear receptor agonists to induce CYP activity.
Conclusion
Our systematic scoping review offers an evidence-based overview and evaluation of the current state of research on bioprinted liver models, representing a promising and innovative technology for creating alternative organ models. We conducted a thorough examination of both the methodological and technical facets of model development and scrutinized the reporting quality within the realm of bioprinted liver models. This systematic scoping review can serve as a valuable template for systematically evaluating the progress of organ model development in various other domains. The transparently derived evidence presented here can provide essential support to the research community, facilitating the adaptation of technological advancements, the establishment of standards, and the enhancement of model robustness. This is particularly crucial as we work toward the long-term objective of establishing new approach methods as reliable alternatives to animal testing, with extensive and versatile applications.
... Rats that received amnion derived stem cells had markedly reduced hepatic inflammation and oxidative stress/improved liver function in rats receiving hAMSCs [114] Human amniotic membrane patch Bile duct ligated Rats AM patch could attenuate the severity of biliary fibrosis for longer periods [115] Human amniotic epithelial cells (hAECs) Bile duct ligated Rats Reduced fibroblast numbers/reduced activation of portal fibroblast [116] Acellular human amniotic membrane CCL 4 treated mice Functional acellular human amniotic membrane-hepatocytes grafts integrated with the liver decreases the acute liver injury of mice [79] ...
Liver is a vital organ responsible for metabolic and digestive functions, protein synthesis, detoxification, and numerous other necessary functions. Various acute, chronic, and neoplastic disorders affect the liver and hamper its biological functions. Most of the untreated liver diseases lead to inflammation and fibrosis which develop into cirrhosis. The human amniotic membrane (hAM), the innermost layer of the fetal placenta, is composed of multiple layers that include growth-factor rich basement membrane, epithelial and mesenchymal stromal cell layers. hAM possesses distinct beneficial anti-fibrotic, anti-inflammatory and pro-regenerative properties via the secretion of multiple potent trophic factors and/or direct differentiation into hepatic cells which place hAM-based therapies as potential therapeutic strategies for the treatment of chronic liver diseases. Decellularized hAM is also an ideal scaffold for liver tissue engineering as this biocompatible niche provides an excellent milieu for cell proliferation and hepatocytic differentiation. Therefore, the current review discusses the therapeutic potential of hAM and its derivatives in providing therapeutic solutions for liver pathologies including acute liver failure, metabolic disorders, liver fibrosis as well as its application in liver tissue engineering.
... Some studies just utilized AECs as a vector to carry therapeutic genes for immunodeficient liver diseases but did not detect whether these cells replenished the parenchyma of the liver (Saha & Jaenisch, 2009;Touboul et al., 2010). In liver fibrosis, AECs may block the activation of hepatic stellate cells and macrophages, acting as immunomodulators (Kuk et al., 2019) rather than replenishing the liver's parenchyma (Cargnoni et al., 2018). These studies suggest fetal stem cells act in vivo in a complex way, and how to limit their use to predicted results is unknown. ...
Liver diseases are a major health issue, and prolonged liver injury always progresses. Advanced liver disorders impair liver regeneration. Millions of patients die yearly worldwide, even with the available treatments of liver transplantation and artificial liver support system. With its abundant cell resources and significant differentiative potential, stem cell therapy is a viable treatment for various disorders and offers hope to patients waiting for orthotopic liver transplantation. Considering such plight, stem cell therapeutic strategies deliver hope to the patients. Moreover, we conclude intrinsic and acquired perspectives based on stem cell sources. The properties and therapeutic uses of these stem cells' specific types or sources were then reviewed. Owing to the recent investigations of the above cells, a safe and effective therapy will emerge for advanced liver diseases soon.
... Human AM possesses unique biological properties exerting anti-inflammatory, low immunogenicity, antifibrotic, antimicrobial, and antimutagenic effects 8,[11][12][13] and it is a source of growth factors, cytokines, and cells with stemness properties 2,3 . Thanks to advances in stem cell-based approaches, human amniotic epithelial cells (hAECs) have been widely studied for the treatment of various diseases 14 , such as lung and liver injury and fibrosis, diabetes, acute kidney failure, cardiovascular diseases, wound healing, and premature ovarian failure (POF) [15][16][17][18][19][20][21] . Despite the great therapeutic potential of these cells, preservation and transplantation difficulties make the effective use of hAECs problematic 22,23 . ...
The potential clinical applications of human amniotic membrane (hAM) and human amniotic epithelial cells (hAECs) in the field of regenerative medicine have been known in literature since long. However, it has yet to be elucidated whether hAM contains different anatomical regions with different plasticity and differentiation potential. Recently, for the first time, we highlighted many differences in terms of morphology, marker expression, and differentiation capabilities among four distinct anatomical regions of hAM, demonstrating peculiar functional features in hAEC populations. The aim of this study was to investigate in situ the ultrastructure of the four different regions of hAM by means of transmission electron microscopy (TEM) to deeply understand their peculiar characteristics and to investigate the presence and localization of secretory products because to our knowledge, there are no similar studies in the literature. The results of this study confirm our previous observations of hAM heterogeneity and highlight for the first time that hAM can produce extracellular vesicles (EVs) in a heterogeneous manner. These findings should be considered to increase efficiency of hAM applications within a therapeutic context.
... The AEC secretome counteracts the action of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8), and interferon-gamma (IFN-γ), and reduces the expression of matrix metalloproteinase [64]. AECs also prove able to reduce local fibrosis and collagen deposition in animal models of lung and hepatic fibrosis, by inhibition of transforming growth factor-beta (TGF-β) signal [65,66]. ...
Human term placenta and other postpartum-derived biological tissues are promising sources of perinatal cells with unique stem cell properties. Among the massive current research on stem cells, one medical focus on easily available stem cells is to exploit them in the design of immunotherapy protocols, in particular for the treatment of chronic non-curable human diseases. Type 1 diabetes is characterized by autoimmune destruction of pancreatic beta cells and perinatal cells can be harnessed both to generate insulin-producing cells for beta cell replenishment and to regulate autoimmune mechanisms via immunomodulation capacity. In this study, the strong points of cells derived from amniotic epithelial cells and from umbilical cord matrix are outlined and their potential for supporting cell therapy development. From a basic research and expert stem cell point of view, the aim of this review is to summarize information regarding the regenerative medicine field, as well as describe the state of the art on possible cell therapy approaches for diabetes.
... Specifically, hAESCs have very low immunogenicity, thus are suitable for allotransplantation. Indeed, mounting studies have revealed the beneficial outcomes of hAESCs-based therapy for wound healing (Zhao et al., 2018;Zheng et al., 2018), skin graft (Li et al., 2012), injury repair (Kamiya et al., 2005;Parmar et al., 2006;Bai et al., 2020), pulmonary and liver fibrosis (Manuelpillai et al., 2012;Tan et al., 2014;Miki, 2016;Tan et al., 2017;Cargnoni et al., 2018), and importantly in neurological diseases (Di Germanio et al., 2016;Sanluis-Verdes et al., 2017), including spinal cord injury (Gao et al., 2014), Parkinson's disease (Yang et al., 2010), Alzheimer's disease (AD) (Xue et al., 2012;Kim et al., 2020), and multiple sclerosis (McDonald et al., 2011;Liu et al., 2012). However, successful clinical outcomes of hAESC transplantation depend on its immunomodulating functions. ...
Stem cells isolated from perinatal tissue sources possess tremendous potential for biomedical and clinical applications. On the other hand, emerging data have demonstrated that bioactive natural compounds regulate numerous cellular and biochemical functions in stem cells and promote cell migration, proliferation, and attachment, resulting in maintaining stem cell proliferation or inducing controlled differentiation. In our previous studies, we have reported for the first time that various natural compounds could induce targeted differentiation of hAESCs in a lineage-specific manner by modulating early biological and molecular events and enhance the therapeutic potential of hAESCs through modulating molecular signaling. In this perspective, we will discuss the advantages of using naturally occurring active compounds in hAESCs and their potential implications for biological research and clinical applications.
... Recent studies have shown that the application of hAECs in animal models of many diseases has achieved good therapeutic effects, including lung injury and liver fibrosis (Cargnoni et al., 2018;Tan et al., 2018). It has been reported that in chemotherapyinduced premature ovarian failure, exosomes (EXOs) derived from hAECs can inhibit apoptosis by transferring miRNAs and restore ovarian function (Zhang et al., 2019). ...
... It is thus required to explore new methods for the treatment of cisplatin-AKI without interfering with its anti-cancer effects. The reparative therapeutic potential of hAECs have been assessed in a multitude of experimental animal models including lung injury, brain injury, hepatic fibrosis, and multiple sclerosis (Kakishita et al., 2000;McDonald et al., 2015;Cargnoni et al., 2018;Tan et al., 2018). To date, only a few applications of hAECs in renal injury have been reported. ...
Background: Cisplatin is a widely used chemotherapeutic drug, whereas the clinical application is greatly limited by its nephrotoxic side effect. Currently, there has been no effective treatment to prevent cisplatin-induced acute kidney injury (cisplatin-AKI). Human amniotic epithelial cells (hAECs) and their derived exosomes (EXOs) have been proven to effectively protect against ischemia reperfusion-induced AKI, yet their roles in cisplatin-AKI are still unknown.
Methods: C57BL/6J mice were given two doses of cisplatin at 20 or 15 mg/kg of body weight to induce AKI with or without mortality. hAECs or EXOs were injected via tail vein 1 day after cisplatin administration. Serum and kidney tissues were collected on the fourth day after 15 mg/kg cisplatin treatment to explore the nephro-protective effects of hAECs and EXOs on cisplatin-AKI. Lung cancer xenograft model was built by subcutaneous injection of A549 cells into BALB/c nude mice to evaluate the effect of hAECs or EXOs on cisplatin chemotherapy.
Results: Cisplatin nephrotoxicity was significantly attenuated by hAECs and EXOs as evidenced by reduced mortality rate and decreased serum creatinine (sCr) and reduced tubular injury score. hAECs or EXOs exerted the nephro-protective effects via suppression of TNF-α/MAPK and caspase signaling pathways. In the A549 lung cancer xenograft mouse model, administration of hAECs or EXOs did not promote tumor growth or compromise the therapeutic effects of cisplatin on tumors.
Conclusion: This study is the first to demonstrate that hAECs and their derived exosomes have nephro-protective effects in cisplatin-AKI in vivo . Importantly, neither hAECs nor EXOs compromise the antitumor activity of cisplatin. These results potentially support the use of hAECs and their derived EXOs as nephro-protectors against cisplatin-induced nephrotoxicity clinically.
... Ductal epithelial cells line the bile ducts. Reprinted with permission from [202]. Copyright 2017 Wiley air-blood barrier (ABB) and gastrointestinal tract (GIT) barrier. ...
The widespread use of nanomaterials (NMs) has raised concerns that exposure to them may introduce potential risks to the human body and environment. The liver is the main target organ for NMs. Hepatotoxic effects caused by NMs have been observed in recent studies but have not been linked to liver disease, and the intrinsic mechanisms are poorly elucidated. Additionally, NMs exhibit varied toxicokinetics and induce enhanced toxic effects in susceptible livers; however, thus far, this issue has not been thoroughly reviewed. This review provides an overview of the toxicokinetics of NMs. We highlight the possibility that NMs induce hepatic diseases, including nonalcoholic steatohepatitis (NASH), fibrosis, liver cancer, and metabolic disorders, and explore the underlying intrinsic mechanisms. Additionally, NM toxicokinetics and the potential induced risks in the livers of susceptible individuals, including subjects with liver disease, obese individuals, aging individuals and individuals of both sexes, are summarized. To understand how NM type affect their toxicity, the influences of the physicochemical and morphological (PCM) properties of NMs on their toxicokinetics and toxicity are also explored. This review provides guidance for further toxicological studies on NMs and will be important for the further development of NMs for applications in various fields.
... hAEC were used in the treatment of experimental liver failure in several animal models with native amniotic epithelial cells [144][145][146][147], hAEC culture media containing their secretory products [143], and epithelial cells partially differentiated towards human hepatocytes [113]. Each of these approaches has its advantages and limitations, nevertheless, they resulted in improved liver functioning (Table 6). ...
... & hAEC reduce TGFβ synthesis. This leads to inhibition of myofibroblasts derived from HSC, thereby reducing ECM production [145]. & Substances secreted by hAEC into their niche act antifibrotically in a paracrine manner [148,149]. ...
... Preclinical trials using the native afterbirth MSC and hAEC resulted in improved liver function in animals, and the cells given became similar to hepatocytes over time, thus, to some extent, restored its structure [180]. Afterbirth cells reduced the inflammatory process associated with liver damage by inhibiting the production of inflammatory cytokines and secretion of anti-inflammatory cytokines, thus reducing the cell apoptosis and necrotic areas, and inhibited liver fibrosis [145,156,175]. Positive effects observed in animals led to clinical trials in humans. ...
Toxic, viral and surgical injuries can pose medical indications for liver transplantation. The number of patients waiting for a liver transplant still increases, but the number of organ donors is insufficient. Hepatocyte transplantation was suggested as a promising alternative to liver transplantation, however, this method has some significant limitations. Currently, afterbirth tissues seem to be an interesting source of cells for the regenerative medicine, because of their unique biological and immunological properties. It has been proven in experimental animal models, that the native stem cells, and to a greater extent, hepatocyte-like cells derived from them and transplanted, can accelerate regenerative processes and restore organ functioning. The effective protocol for obtaining functional mature hepatocytes in vitro is still not defined, but some studies resulted in obtaining functionally active hepatocyte-like cells. In this review, we focused on human stem cells isolated from placenta and umbilical cord, as potent precursors of hepatocyte-like cells for regenerative medicine. We summarized the results of preclinical and clinical studies dealing with the introduction of epithelial and mesenchymal stem cells of the afterbirth origin to the liver failure therapy. It was concluded that the use of native afterbirth epithelial and mesenchymal cells in the treatment of liver failure could support liver function and regeneration. This effect would be enhanced by the use of hepatocyte-like cells obtained from placental and/or umbilical stem cells.
Graphical abstract
... In line with this, preclinical studies have shown that administration of perinatal cells or their secretome induces therapeutic effects in many models of inflammatory diseases such as liver (Lee et al., 2010;Manuelpillai et al., 2010Manuelpillai et al., , 2012Jung et al., 2013;Cargnoni et al., 2018), and lung fibrosis FIGURE 2 | Immunomodulatory effects of perinatal-MSC extracellular vesicles (EVs). The molecular content of perinatal MSC-EVs represented by proteins, lipids, and nucleic acids can strongly affect both the innate (neutrophils and macrophages) and adaptive immune response (T lymphocytes). ...
Perinatal cells, including cells from placenta, fetal annexes (amniotic and chorionic membranes), umbilical cord, and amniotic fluid display intrinsic immunological properties which very likely contribute to the development and growth of a semiallogeneic fetus during pregnancy. Many studies have shown that perinatal cells can inhibit the activation and modulate the functions of various inflammatory cells of the innate and adaptive immune systems, including macrophages, neutrophils, natural killer cells, dendritic cells, and T and B lymphocytes. These immunological properties, along with their easy availability and lack of ethical concerns, make perinatal cells very useful/promising in regenerative medicine. In recent years, extracellular vesicles (EVs) have gained great interest as a new therapeutic tool in regenerative medicine being a cell-free product potentially capable, thanks to the growth factors, miRNA and other bioactive molecules they convey, of modulating the inflammatory microenvironment thus favoring tissue regeneration. The immunomodulatory actions of perinatal cells have been suggested to be mediated by still not fully identified factors (secretoma) secreted either as soluble proteins/cytokines or entrapped in EVs. In this review, we will discuss how perinatal derived EVs may contribute toward the modulation of the immune response in various inflammatory pathologies (acute and chronic) by directly targeting different elements of the inflammatory microenvironment, ultimately leading to the repair and regeneration of damaged tissues.
