Figure 5 - available from: Journal of Translational Medicine
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ERCs suppress CD4 + and CD8 + T cell populations in the spleen and kidney. Flow cytometric analysis of CD4 + and CD8 + T cell populations was performed in the a spleen and b kidney of the sham, IRI-untreated and ERC-treated groups. c Treatment with ERCs significantly decreased the percentages of CD4 + and CD8 + T cells in the spleen and kidney. Bar graphs represent mean ± SD of three separate experiments. p values were determined by one-way ANOVA. Data shown are a representative of three separate experiments performed (*p < 0.01, vs. IRI-untreated group, n = 6)
Source publication
Endometrial regenerative cells (ERCs) is an attractive novel type of adult mesenchymal stem cells that can be non-invasively obtained from menstrual blood and are easily replicated at a large scale without tumorigenesis. We have previously reported that ERCs exhibit unique immunoregulatory properties in experimental studies in vitro and in vivo. In...
Citations
... Compared with other MSCs, MenSCs have unique advantages, including periodic acquisition, non-invasiveness, convenience, and no ethical disputes. Similar to other MSCs, MenSCs play an immunomodulatory role by promoting the polarization of macrophages from the M1 phenotype to the M2 phenotype, increasing the number of regulatory T cells, promoting the secretion of anti-inflammatory factors IL-10 and IL-4, and inhibiting the expression of inflammatory factors interleukin-1, tumor necrosis factor-α, and interferon-γ [11,12].In our previous study, we found that MenSCs could reduce the blood glucose level in diabetic mice. However, the blood glucose of the mice did not return to baseline [13]. ...
Diabetes imposes a huge burden worldwide. Islet transplantation is an alternative therapy for diabetes. However, tacrolimus, a kind of immunosuppressant after organ transplantation, is closely related to post-transplant diabetes mellitus. Mesenchymal stem cells (MSCs) have attracted interest for their potential to alleviate diabetes. In vivo experiments revealed that human menstrual blood-derived stem cells (MenSCs) treatment improved tacrolimus-induced blood glucose, body weight, and glucose tolerance disorders in mice. RNA sequencing was used to analyze the potential therapeutic targets of MenSCs. In this study, we illustrated that cystathionine β-synthase (CBS) contributed to tacrolimus -induced islet dysfunction. Using β-cell lines (MIN6, β-TC-6), we demonstrated that MenSCs ameliorated tacrolimus-induced islet dysfunction in vitro. Moreover, MenSC reduced the tacrolimus-induced elevation of CBS levels and significantly enhanced the viability, anti-apoptotic ability, glucose-stimulated insulin secretion (GSIS), and glycolytic flux of β-cells. We further revealed that MenSCs exerted their therapeutic effects by inhibiting CBS expression to activate the IL6/JAK2/STAT3 pathway. In conclusion, we showed that MenSCs may be a potential strategy to improve tacrolimus-induced islet dysfunction.
... Limitations of this approach include lack of reproducibility, interobserver variability and limited sample analysis. Additionally, the systems used may differ in terms of the morphological structures and areas that are analysed (Hesketh et al., 2014;Sun et al., 2016;Wang et al., 2005). Here, we have developed a novel system to quantify kidney damage in a mouse model of IRI by using a DL approach. ...
... Two pathological classes, namely "Intratubular casts" and "Tubular necrosis", were considered reliable and were further used to score damage in the mouse kidney sections. These two classes represent the most widely used parameters in different scoring systems to identify acute IRI changes (Hesketh et al., 2014;Sun et al., 2016;Wang et al., 2005). Necrosis, in particular, overlapped as expected with OSOM in most samples, as mentioned in previous studies (Hesketh et al., 2014;Wang et al., 2005). ...
... Heatmaps were drawn based on the quantification of "Intratubular casts" and "Tubular necrosis" of each grid patch. As expected, most of the damage was localised in the OSOM region of the kidney (Hesketh et al., 2014;Sun et al., 2016;Wang et al., 2005). However, in several cases, a substantial amount of damage (mainly cast formation) was visually identified in cortical and medullary areas, indicating that traditional scoring systems that analyse fields of view only from the cortex or only from the OSOM might not provide the most accurate assessment. ...
This study focuses on ischaemia-reperfusion injury (IRI) in kidneys, a
cause of acute kidney injury (AKI) and end-stage kidney disease
(ESKD). Traditional kidney damage assessment methods are semiquantitative
and subjective. This study aims to use a convolutional
neural network (CNN) to segment murine kidney structures after IRI,
quantify damage via CNN-generated pathological measurements,
and compare this to conventional scoring. The CNN was able to
accurately segment the different pathological classes, such as
Intratubular casts and Tubular necrosis, with an F1 score of over
0.75. Some classes, such as Glomeruli and Proximal tubules, had
even higher statistical values with F1 scores over 0.90. The scoring
generated based on the segmentation approach statistically
correlated with the semiquantitative assessment (Spearman’s rank
correlation coefficient=0.94). The heatmap approach localised the
intratubular necrosis mainly in the outer stripe of the outer medulla,
while the tubular casts were also present in more superficial or deeper
portions of the cortex and medullary areas. This study presents a
CNN model capable of segmenting multiple classes of interest,
including acute IRI-specific pathological changes, in a whole mouse
kidney section and can provide insights into the distribution of
pathological classes within the whole mouse kidney section.
... Macrophages are the main source of cytokines, chemokines and growth factors that guide inflammation and repair after skeletal muscle injury [41], and exhibit two phenotypes with different functions: the classically activated subtype (M1) displays a proinflammatory profile, and the alternatively activated subtype (M2) exhibits anti-inflammatory and tissue repair properties [42]. Previous studies have shown that other sources of MSCs have beneficial effects on IRI-related injury by facilitating the transformation of M1-type macrophages to M2-type macrophages [43][44][45], and experiments showed that M1 macrophages co-cultured with MSCs acquired an M2 phenotype [46]. However, the role of macrophages in ESC-MSCs treated IRI-related skeletal muscle injury, such as that in ACS, remains unclear. ...
Background
Acute compartment syndrome (ACS), a well-known complication of musculoskeletal injury, results in muscle necrosis and cell death. Embryonic stem cell-derived mesenchymal stem cells (ESC-MSCs) have been shown to be a promising therapy for ACS. However, their effectiveness and potentially protective mechanism remain unknown. The present study was designed to investigate the efficacy and underlying mechanism of ESC-MSCs in ACS-induced skeletal muscle injury.
Method
A total of 168 male Sprague–Dawley (SD) rats underwent 2 h of intracompartmental pressure elevation by saline infusion into the anterior compartment of the left hindlimb to establish the ACS model. ESC-MSCs were differentiated from the human embryonic stem cell (ESC) line H9. A dose of 1.2 × 10 ⁶ of ESC-MSCs was intravenously injected during fasciotomy. Post-ACS assessments included skeletal edema index, serum indicators, histological analysis, apoptosis, fibrosis, regeneration, and functional recovery of skeletal muscle. Then, fluorescence microscopy was used to observe the distribution of labeled ESC-MSCs in vivo, and western blotting and immunofluorescence analyses were performed to examine macrophages infiltration in skeletal muscle. Finally, we used liposomal clodronate to deplete macrophages and reassess skeletal muscle injury in response to ESC-MSC therapy.
Result
ESC-MSCs significantly reduced systemic inflammatory responses, ACS-induced skeletal muscle edema, and cell apoptosis. In addition, ESC-MSCs inhibited skeletal muscle fibrosis and increased regeneration and functional recovery of skeletal muscle after ACS. The beneficial effects of ESC-MSCs on ACS-induced skeletal muscle injury were accompanied by a decrease in CD86-positive M1 macrophage polarization and an increase in CD206-positive M2 macrophage polarization. After depleting macrophages with liposomal clodronate, the beneficial effects of ESC-MSCs were attenuated.
Conclusion
Our findings suggest that embryonic stem cell-derived mesenchymal stem cells infusion could effectively alleviate ACS-induced skeletal muscle injury, in which the beneficial effects were related to the regulation of macrophages polarization.
... In this study, we have shown that UDCs contribute to regeneration of renal tubules and improve kidney function in mice with renal ischemia-reperfusion injuries; our data support a potential role for mesenchymal stem cells in repair of damaged kidneys. Our findings are in line with previous work showing human endometrial regenerative cells from menstrual blood attenuated renal ischemia-reperfusion injury in mice by anti-inflammatory and immune-regulatory effects [40]. Interestingly, our data strongly suggest UDCs as one of the origins of tubular regeneration and recovery, which was confirmed by double positive staining of LTA and DsRed. ...
Background
Acute kidney injury (AKI) causes abrupt deterioration in kidney function that disrupts metabolic, electrolyte and fluid homeostasis. Although the prevalence of AKI is steadily increasing, no definitive treatment options are available, leading to severe morbidity and mortality. We evaluated the role of uterine-derived multipotent stem cells in kidney regeneration after ischemic AKI.
Methods
Female C57BL/6J mice were hysterectomized and subsequently subject to AKI by either unilateral or bilateral renal ischemia–reperfusion injury. Uterine-derived cells (UDCs), containing a population of uterine stem cells, were isolated from the uteri of female transgenic DsRed mice and injected intravenously to AKI mice. Engraftment of DsRed cells was analyzed by flow cytometry while serum creatinine levels were determined colorimetrically. Expression of UDC markers and cytokine markers were analyzed by immunohistochemical and qRT-PCR methods, respectively. The Kaplan–Meier method was used to analyze survival time while unpaired t test with Welch’s correction used for data analysis between two groups.
Results
Mice with an intact uterus, and hence an endogenous source of UDCs, had a higher survival rate after bilateral ischemic AKI compared to hysterectomized mice. Mice treated with infusion of exogenous UDCs after hysterectomy/AKI had lower serum creatinine levels and higher survival rates compared to controls that did not receive UDCs. Engraftment of labeled UDCs was significantly higher in kidneys of bilateral ischemic AKI mice compared to those that underwent a sham surgery. When unilateral ischemic AKI was induced, higher numbers of UDCs were found in the injured than non-injured kidney. Immunofluorescence staining demonstrated double-positive DsRed/Lotus tetragonolobus agglutinin (LTA) positive cells and DsRed/CD31 positive cells indicating contribution of UDCs in renal tubular and vascular regeneration. Expression of Cxcl12 , Bmp2 , Bmp4 , and Ctnf in renal tissue was significantly higher in the UDCs injection group than the control group.
Conclusions
UDCs engrafted injured kidneys, contributed to proximal tubule and vascular regeneration, improved kidney function and increased survival in AKI mice. UDC administration is a promising new therapy for AKI. Endogenous uterine stem cells likely also preserve kidney function, suggesting a novel interaction between the uterus and kidney. We suggest that hysterectomy may have a detrimental effect on response to renal injury.
... In addition to the above pathological conditions, animal experiments showed that menstrual-blood MSCs demonstrated therapeutic efficacy in ischemia of the lower extremities; Parkinson's disease; allergic encephalitis (Rodrigues et al., 2016); ischemic stroke (Chen et al., 2019); injuries to the spinal cord (Wu et al., 2018), peripheral nerves (Farzamfar et al., 2017), and endometrium (Hu et al., 2019); graft-versus-host reactions (Luz-Crawford et al., 2016); ischemia-reperfusion of the kidney (Sun et al., 2016); and osteochondral defects (Khanmohammadi et al., 2019). The first case of the clinical use of these cells was their transplantation into four patients with multiple sclerosis, which showed the safety of their introduction (Zhong et al., 2009). ...
Development of regenerative medicine creates the need for an accessible source of cells for stimulation of the recovery processes in pathologically altered tissues and organs. Such a source can be menstrual blood with fragments of the desquamated endometrium containing mesenchymal stromal cells (MSCs) that are involved in the regeneration of endometrial functional layer during the menstrual cycle. These cells are phenotypically similar to MSCs from other clinically relevant sources (bone marrow, adipose tissue, dental pulp, placenta) capable of active growth in vitro, have a wide differentiation potential. They secrete various biologically active substances in a paracrine manner and thereby stimulate survival and proliferation of cells in affected tissues, regulate immune responses and angiogenesis, and prevent fibrosis. Currently, the possibility to use menstrual blood-derived MSCs in various fields of medicine is actively researched. Experiments on animals demonstrated the prospects of cell therapy with these cells for the treatment of pathologies of the cardiovascular, nervous, reproductive systems, skin wounds, myodystrophy, diabetes mellitus, diseases of the liver, lungs, intestines and other organs. However, in order to successfully implement menstrual blood-derived MSCs in medical practice, further research is required to optimize protocols for cells isolation, assess possible risks of their transplantation, overcoming the problem of their low survival in the lesion focus and clarify the cellular and molecular mechanisms of their regenerative effect. The objectives of this review are to analyze and systematize the accumulated knowledge about the therapeutic potential of menstrual blood-derived MSCs that is necessary for their effective clinical use.
... Endometrial regenerative cells (ERCs) from menstrual blood played as a new source of adult stem cells and not only have the potential of self-renewal [13], mesenchymal stem cell-(MSC-) like phenotype [14], and immune modulation [15] but also have the unique advantages of noninvasiveness, relatively unlimited source, strong proliferation ability, and avoiding ethical problems [16,17]. Our and others' previous studies have demonstrated that ERCs could modulate immune homeostasis in acute hepatitis and other models, such as heterotopic heart transplantation and kidney ischemia reperfusion injury in mice via different pathways [18][19][20][21][22]. In ulcerative colitis, ERCs can not only regulate colitis but also be modified for better therapeutic effects [21,23]. ...
Background:
Traditional interventions can play a certain role in attenuating ulcerative colitis (UC), known as one type of inflammatory bowel diseases, but sometimes are not effective. Endometrial regenerative cells (ERCs) have been shown to exert immunosuppressive effects in different models of inflammation, and stem cell-derived conditioned media (CM) have advantages over cell therapy in terms of easy access and direct action. However, whether ERC-CM could alleviate colitis remains unclear and will be explored in this study.
Methods:
Menstrual blood was collected from healthy female volunteers to obtain ERCs and ERC-CM. Acute colitis was induced by 3% dextran sodium sulfate (DSS), and ERC-CM was injected on days 4, 6, and 8, respectively, after induction. The disease activity index was calculated through the record of weight change, bleeding, and fecal viscosity during the treatment process. Histological features, macrophage and CD4+ T cell in the spleen and colon, and cytokine profiles in the sera and colon were measured. In addition, an in vitro lymphocyte proliferation assay was measured by using a CCK-8 kit in this study.
Results:
ERC-CM treatment significantly improved the symptoms and histological changes in colitis mice. ERC-CM increased the percentage of Tregs in the spleen and colon but decreased the percentages of M1 macrophages and Th1 and Th17 cells in the spleen and decreased the population of Th17 cells in the colon. In addition, ERC-CM treatment decreased the local expression of TNF-α, IL-6, and iNOS in the colon. Furthermore, ERC-CM increased the levels of anti-inflammatory cytokines IL-10 and IL-27 but decreased proinflammatory cytokines IL-6 and IL-17 in the sera. In addition, ERC-CM significantly inhibited ConA-induced mouse lymphocyte proliferation in vitro.
Conclusion:
The results suggest that ERC-CM can exert similar therapeutic effects as ERCs and could be explored for future application of cell-free therapy in the treatment of colitis.
... And no side effects have been reported related to ERC treatment [14]. Previous studies performed by our research group and others have also shown that ERCs have therapeutic effects in a variety of disease models, such as cardiac transplantation [15], renal ischemia-reperfusion injury [16], and inflammatory bowel disease [17], etc. However, their therapeutic effects and regulatory mechanisms in AIH are still unclear. ...
Background
Autoimmune hepatitis (AIH) is a T cell-mediated immune disease that activates abnormally against hepatic antigens. We have previously reported that endometrial regenerative cells (ERCs) were a novel source of adult stem cells, which exhibiting with powerful immunomodulatory effects. Galectin-9 (Gal-9) is expressed in ERCs and plays an important role in regulating T cell response. This study aims to explore the role of ERCs in attenuation of AIH and to determine the potential mechanism of Gal-9 in ERC-mediated immune regulation.
Methods
ERCs were obtained from menstrual blood of healthy female volunteers. In vitro, ERCs were transfected with lentivirus vectors carrying LGALS9 gene and encoding green fluoresce protein (GFP-Gal-9-LVs) at a MOI 50, Gal-9 expression in ERCs was detected by ELISA and Q-PCR. CD4 ⁺ T cells isolated from C57BL/6 mouse spleen were co-cultured with ERCs. The proliferation of CD4 ⁺ T cells was detected by CCK-8 kit and the level of Lck/zap-70/LAT protein was measured by western blot. Furthermore, AIH was induced by ConA in C57BL/6 mice which were randomly assigned to untreated, unmodified ERC-treated and Gal-9 high-expressing ERC-treated groups. Histopathological score, liver function, CD4 ⁺ /CD8 ⁺ cell infiltration in liver tissues, the proportion of immune cells in the spleen and liver, and ERC tracking were performed accordingly to assess the progression degree of AIH.
Results
After transfecting with GFP-Gal-9-LVs, Gal-9 expression in ERCs was significantly increased. Additionally, Gal-9 high-expressing ERCs effectively inhibited CD4 ⁺ T cell proliferation and downregulated CD4 ⁺ T cell active related proteins p-Lck/p-ZAP70/p-LAT in vitro. Furthermore, treatment with Gal-9 high-expressing ERCs restored liver function, ameliorated liver pathological damage, inhibit CD4 ⁺ and CD8 ⁺ T cell proliferation and suppress Th1 and Th17 cell response in the hepatitis mice. In addition, Gal-9 high-expressing ERCs further markedly enhanced the level of IL-10 but reduced the levels of IFN-γ, TNF-α, and IL-4 in mouse sera and liver. Cell tracking also showed that ERCs could migrate to the damaged liver organs.
Conclusions
The results suggested that Gal-9 was an essential modulator, which was required by ERCs in regulating T cell response and attenuating ConA-induced experimental hepatitis. And also, it provides a novel idea for the clinical treatment of AIH.
... Most importantly, any significant side effects including acute, subchronic, or chronic poisoning, infection, tumorigenesis, or endometriosis has not been reported either in preclinical studies or in clinical studies during the treatments of various diseases with MenSCs over the past yeas [54][55][56] (Table 2). Rat model [151] Endometrial injury Mice model [152] Premature ovarian failure Rat model [58] Mice model [59,78] Liver failure Mice model [60][61][62] Pig model [153] Liver fibrosis Mice model [154] Experimental stroke In vitro stroke model of oxygen glucose deprivation [63] Pulmonary fibrosis Mice model [64,65] ARDS Patients with H7N9-induced ARDS [71] Myocardial infarction Rat model [46,68] Cardiac allograft Mice model [67,90] Alzheimer's disease Mice model [69] Acute lung injury Mice model [70] Renal ischemia reperfusion injury Mice model [72] Type 1 diabetes Mice model [75] Chronic nonhealing wounds Diabetic mice model [74] Sciatic nerve injury Rat model [73] Existing studies have found that MenSCs therapy may be an attractive alternative approach for intrauterine adhesion (IUA) [57], premature ovarian failure (POF) [58,59], liver failure [60][61][62], experimental stroke [63], pulmonary fibrosis [64,65], cardiac diseases [66,67], myocardial infarction [46,68], Alzheimer's disease [69], acute lung injury [70], acute respiratory distress syndrome [71], renal ischemia reperfusion injury [72], sciatic nerve injury [73], chronic nonhealing wounds [74], and type 1 diabetes [75] ( Table 2). Studies reported that MenSCs may be used for patients with severe IUA. ...
... Most importantly, any significant side effects including acute, subchronic, or chronic poisoning, infection, tumorigenesis, or endometriosis has not been reported either in preclinical studies or in clinical studies during the treatments of various diseases with MenSCs over the past yeas [54][55][56] (Table 2). Rat model [151] Endometrial injury Mice model [152] Premature ovarian failure Rat model [58] Mice model [59,78] Liver failure Mice model [60][61][62] Pig model [153] Liver fibrosis Mice model [154] Experimental stroke In vitro stroke model of oxygen glucose deprivation [63] Pulmonary fibrosis Mice model [64,65] ARDS Patients with H7N9-induced ARDS [71] Myocardial infarction Rat model [46,68] Cardiac allograft Mice model [67,90] Alzheimer's disease Mice model [69] Acute lung injury Mice model [70] Renal ischemia reperfusion injury Mice model [72] Type 1 diabetes Mice model [75] Chronic nonhealing wounds Diabetic mice model [74] Sciatic nerve injury Rat model [73] Existing studies have found that MenSCs therapy may be an attractive alternative approach for intrauterine adhesion (IUA) [57], premature ovarian failure (POF) [58,59], liver failure [60][61][62], experimental stroke [63], pulmonary fibrosis [64,65], cardiac diseases [66,67], myocardial infarction [46,68], Alzheimer's disease [69], acute lung injury [70], acute respiratory distress syndrome [71], renal ischemia reperfusion injury [72], sciatic nerve injury [73], chronic nonhealing wounds [74], and type 1 diabetes [75] ( Table 2). Studies reported that MenSCs may be used for patients with severe IUA. ...
Endometrial stem/progenitor cells have been proved to exist in periodically regenerated female endometrium and can be divided into three categories: endometrial epithelial stem/progenitor cells, CD140b ⁺ CD146 ⁺ or SUSD2 ⁺ endometrial mesenchymal stem cells (eMSCs), and side population cells (SPs). Endometrial stem/progenitor cells in the menstruation blood are defined as menstrual stem cells (MenSCs). Due to their abundant sources, excellent proliferation, and autotransplantation capabilities, MenSCs are ideal candidates for cell-based therapy in regenerative medicine, inflammation, and immune-related diseases. Endometrial stem/progenitor cells also participate in the occurrence and development of endometriosis by entering the pelvic cavity from retrograde menstruation and becoming overreactive under certain conditions to form new glands and stroma through clonal expansion. Additionally, the limited bone marrow mesenchymal stem cells (BMDSCs) in blood circulation can be recruited and infiltrated into the lesion sites, leading to the establishment of deep invasive endometriosis. On the other hand, cell derived from endometriosis may also enter the blood circulation to form circulating endometrial cells (CECs) with stem cell-like properties, and to migrate and implant into distant tissues. In this manuscript, by reviewing the available literature, we outlined the characteristics of endometrial stem/progenitor cells and summarized their roles in immunoregulation, regenerative medicine, and endometriosis, through which to provide some novel therapeutic strategies for reproductive and cancerous diseases.
... Additionally, due to results that cloning efficiency and OCT-4 expression of MenSCs from patients with intrauterine adhesions were lower compared with those from healthy women, this study revealed new possibilities to use MenSCs for the treatment of intrauterine adhesions, which remains one of the most challenging fertility problems until now [8]. Moreover, MenSCs are shown to exert a vascular remodeling role and an immunoregulatory role by inhibiting the expression of proinflammatory factors and promoting so-called T helper type 2 (Th2) cytokines such as interleukin-4 (IL-4), which could play a critical role in the embryo implantation process and successful pregnancy development [3,[9][10][11]. ...
When looking for the causes and treatments of infertility, much attention is paid to one of the reproductive tissues—the endometrium. Therefore, endometrial stem cells are an attractive target for infertility studies in women of unexplained origin. Menstrual blood stem cells (MenSCs) are morphologically and functionally similar to cells derived directly from the endometrium; with dual expression of mesenchymal and embryonic cell markers, they proliferate and regenerate better than bone marrow mesenchymal stem cells. In addition, menstrual blood stem cells are extracted in a non-invasive and painless manner. In our study, we analyzed the characteristics and the potential for decidualization of menstrual blood stem cells isolated from healthy volunteers and women diagnosed with infertility. We demonstrated that MenSCs express CD44, CD166, CD16, CD15, BMSC, CD56, CD13 and HLA-ABC surface markers, have proliferative properties, and after induction of menstrual stem cell differentiation into epithelial direction, expression of genes related to decidualization (PRL, ESR, IGFBP and FOXO1) and angiogenesis (HIF1, VEGFR2 and VEGFR3) increased. Additionally, the p53, p21, H3K27me3 and HyperAcH4 proteins’ expression increased during MenSCs decidualization, they secrete proteins that are involved in the regulation of the actin cytoskeleton, estrogen and relaxin signaling pathways and the management of inflammatory processes. Our findings reveal the potential use of MenSCs for the treatment of reproductive disorders.
... Compared with MSCs, ERCs are with more outstanding advantages, including diverse differentiation potentials, immunomodulatory properties, non-invasive obtaining process, and high proliferative capacity without karyotypic abnormality [16]. We and others have previously reported the forcible therapeutic effects of ERCs on immune-related diseases such as acute liver injury, critical limb ischemia, renal ischemia reperfusion injury, pulmonary fibrosis, myocardial infarction, and so on [17][18][19][20][21][22]. Moreover, no serious immunological rejections were emerging against the human-derived ERCs when they were used to treat animal models [19]. ...
Background
Ulcerative colitis (UC) is a chronic, relapsing, and non-specific inflammatory bowel disease, and the current treatment strategies were mainly used to relieve symptoms or for maintenance. Endometrial regenerative cells (ERCs) are mesenchymal-like stromal cells and have been demonstrated to alleviate multiple immune-dysregulation diseases. Pro-inflammatory stimuli were reported to enhance the immunosuppressive functions of ERCs, but the mechanism underlined is not fully understood. Here, we have designed this study to investigate the therapeutic effects of IL-1β-primed ERCs in the attenuation of experimental colitis.
Methods
BALB/c mice were given 3% dextran sodium sulfate (DSS) for 7 consecutive days and free tap water for 3 days sequentially to induce experimental colitis. PBS (200 μL), ERCs, and IL-1β-primed ERCs (10ng/mL, 48 h) were injected (1 million/mouse/day, i.v. ) on day 2, 5, and 8, respectively. Colonic and splenic samples were harvested on day 10 after DSS induction.
Results
It was found that IL-1β-primed ERC treatment markedly attenuated colonic damage, body weight loss, and colon length shortening in colitis mice. Compared with other treatments, cell populations of CD4 ⁺ IL-4 ⁺ Th2 cells, CD4 ⁺ CD25 ⁺ FOXP3 ⁺ regulatory T cells (Tregs), and CD68 ⁺ CD206 ⁺ macrophages in spleens were also significantly upregulated in the IL-1β-primed ERC-treated group ( p < 0.05). In addition, lower expression of pro-inflammatory (IFN-γ, IL-17, TNF-α, and IL-6), but higher levels of anti-inflammatory cytokines (IL-4 and IL-10) were detected in colons in the IL-1β-primed ERC-treated group ( p < 0.05 vs. other groups). Importantly, we also found that different generations of ERCs had an overall lower secretion of Dickkopf-1 (DKK1) by IL-1β pre-stimulation ( p < 0.05) and a higher expression of β-catenin in colonic and splenic tissues after the administration of IL-1β-primed ERCs.
Conclusions
This study has demonstrated that IL-1β pre-stimulation effectively downregulated DKK1 expression in ERCs, which in turn promoted the wnt/β-catenin pathway activation in colonic and splenic tissues. Consequently, IL-1β-primed ERCs exhibited an enhanced therapeutic effect in the attenuation of DSS-induced colitis.
