scholarly journals Conditioned Medium from Human Amnion-Derived Mesenchymal Stem Cells Regulates Activation of Primary Hepatic Stellate Cells

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Qingjie Fu ◽  
Shunsuke Ohnishi ◽  
Naoya Sakamoto
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Liver Fibrosis ◽  
Conditioned Medium ◽  
Hepatic Stellate Cells ◽  
Collagen Type ◽  
Transforming Growth Factor ◽  
Stellate Cells ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Human Amnion

Mesenchymal stem cells (MSCs), or multipotent mesenchymal stromal cells, are present in almost all organs and tissues, including the amnion. Human amnion-derived mesenchymal stem cell (hAMSC) transplantation has been reported to ameliorate liver fibrosis in animal models. However, the mechanism for the prevention of liver fibrosis is poorly understood. In this study, we investigated the effects, and underlying mechanisms, of a conditioned medium obtained from hAMSC cultures (hAMSC-CM) on a primary culture of rat hepatic stellate cells (HSCs). We observed that in routine culture, hAMSC-CM in HSCs significantly inhibited the expression of alpha-smooth muscle actin (α-SMA), an activation marker of HSCs, and the production of collagen type 1 (COL1), a dominant component of the extracellular matrix (ECM) in the culture medium. In addition, hAMSC-CM upregulated the expression of ECM degradation-related genes, such as metalloproteinase- (Mmp-) 2, Mmp-9, Mmp-13, and tissue inhibitor of metalloproteinase- (Timp-) 1; however, it did not affect the expression of collagen type 1α1 (Col1a1). These regulatory effects on HSCs were concentration-dependent. A cell proliferation assay indicated that hAMSC-CM significantly suppressed HSC proliferation and downregulated the expression of cyclin B (Ccnb), a proliferation-related gene. Transforming growth factor-beta (TGF-β) treatment further activated HSCs and hAMSC-CM significantly inhibited the upregulation of α-Sma and Col1a1 induced by TGF-β. These findings demonstrated that hAMSC-CM can modulate HSC function via secretory factors and provide a plausible explanation for the protective role of hAMSCs in liver fibrosis.

scholarly journals Human placental mesenchymal stem cells ameliorate liver fibrosis in mice by upregulation of Caveolin1 in hepatic stellate cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yunqi Yao ◽  
Zhemin Xia ◽  
Fuyi Cheng ◽  
Qingyuan Jang ◽  
Jiao He ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Liver Fibrosis ◽  
Therapeutic Effect ◽  
Hepatic Stellate Cells ◽  
Time Window ◽  
Stellate Cells ◽  
Therapeutic Benefits ◽  
Placental Mesenchymal Stem Cells

Abstract Background Liver fibrosis (LF) is a common pathological process characterized by the activation of hepatic stellate cells (HSCs) and accumulation of extracellular matrix. Severe LF causes cirrhosis and even liver failure, a major cause of morbidity and mortality worldwide. Transplantation of human placental mesenchymal stem cells (hPMSCs) has been considered as an alternative therapy. However, the underlying mechanisms and the appropriate time window for hPMSC transplantation are not well understood. Methods We established mouse models of CCl4-injured LF and administered hPMSCs at different stages of LF once a week for 2 weeks. The therapeutic effect of hPMSCs on LF was investigated, according to histopathological and blood biochemical analyses. In vitro, the effect of hPMSCs and the secretomes of hPMSCs on the inhibition of activated HSCs was assessed. RNA sequencing (RNA-seq) analysis, real-time PCR array, and western blot were performed to explore possible signaling pathways involved in treatment of LF with hPMSCs. Results hPMSC treatment notably alleviates experimental hepatic fibrosis, restores liver function, and inhibits inflammation. Furthermore, the therapeutic effect of hPMSCs against mild-to-moderate LF was significantly greater than against severe LF. In vitro, we observed that the hPMSCs as well as the secretomes of hPMSCs were able to decrease the activation of HSCs. Mechanistic dissection studies showed that hPMSC treatment downregulated the expression of fibrosis-related genes, and this was accompanied by the upregulation of Caveolin-1 (Cav1) (p < 0.001). This suggested that the amelioration of LF occurred partly due to the restoration of Cav1 expression in activated HSCs. Upregulation of Cav1 can inhibit the TGF-β/Smad signaling pathway, mainly by reducing Smad2 phosphorylation, resulting in the inhibition of activated HSCs, whereas this effect could be abated if Cav1 was silenced in advance by siRNAs. Conclusions Our findings suggest that hPMSCs could provide multifaceted therapeutic benefits for the treatment of LF, and the TGF-β/Cav1 pathway might act as a therapeutic target for hPMSCs in the treatment of LF.

scholarly journals The Potential Safe Antifibrotic Effect of Stem Cell Conditioned Medium and Nilotinib Combined Therapy by Selective Elimination of Rat Activated HSCs

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Ahmed Nabil ◽  
Koichiro Uto ◽  
Faten Zahran ◽  
Reham Soliman ◽  
Ayman A. Hassan ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Conditioned Medium ◽  
Cell Lines ◽  
Hepatic Stellate Cells ◽  
Normal Cell ◽  
Combined Therapy ◽  
Stellate Cells ◽  
Collagen Deposition ◽  
Anti Inflammatory

Hepatic fibrosis is a progressive disease with serious clinical complications that arise from abnormal propagation and activation of multiple inflammatory pathways. Nilotinib is an oral tyrosine kinase inhibitor with antifibrotic activity. Mesenchymal stem cells (MSCs) are blank cells and can differentiate into specific cell types. They have the potential to repair and regenerate cells. MSCs have a special paracrine fashion where they produce special exosomes, microvesicles, and cytokines like IL-6, transforming growth factor-beta (TGF-β), and HGF as well as hepatic stellate cell suppressors. This paracrine fashion can decrease collagen deposition, enhance antifibrotic, anti-inflammatory, and angiogenic activity in vitro and in vivo. In our study, the rat’s hepatic stellate cells (HSCs) in addition to different normal cell lines were treated with Nilotinib alone and in combination with liver mesenchymal stem cells conditioned medium (LMSCs-CM) for 24 h. Mono and combined therapy antifibrotic and cytotoxicity effects were evaluated using different parameters including α-SMA, cytochrome c, P53 expression, collagen deposition, DNA content, oxidative stress parameters, cell viability, and apoptosis by flow cytometry analysis. Our results showed that Nilotinib and LMSCs-CM in combination had a significantly potent antifibrotic and anti-inflammatory effect on activated hepatic stellate cells than Nilotinib alone; otherwise, this combination showed the best safety with minimal cytotoxicity on different normal cell lines.

scholarly journals Human Placental Mesenchymal Stem Cells Ameliorate Liver Fibrosis in Mice by Upregulation of Caveolin1 in Hepatic Stellate Cells

2021 ◽  
Author(s):  
Yunqi Yao ◽  
Zhemin Xia ◽  
Fuyi Cheng ◽  
Qingyuan Jang ◽  
Jiao He ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Liver Fibrosis ◽  
Therapeutic Effect ◽  
Hepatic Stellate Cells ◽  
Culture Supernatant ◽  
Severe Disease ◽  
Stellate Cells ◽  
Therapeutic Benefits ◽  
Placental Mesenchymal Stem Cells

Abstract Background: Liver fibrosis (LF) is a common pathological process characterized by the activation of hepatic stellate cells (HSCs) and accumulation of extracellular matrix. Severe LF causes cirrhosis and even liver failure, a major cause of morbidity and mortality worldwide. Transplantation of human placental mesenchymal stem cells (hPMSCs) has been considered as an alternative therapy, replacing liver transplantation in clinical trials, to treat LF. However, the underlying mechanisms and the appropriate time window for hPMSC transplantation are not well understood. Methods: We established mouse models of CCL4-injured LF, and administered hPMSCs once a week for 2 weeks. The therapeutic effect of hPMSCs on LF was investigated, according to histopathological and blood biochemical analyses. What’s more, the culture supernatant of hPMSCs were isolated, and the effect of the culture supernatant on the inhibition of activated HSCs was also assessed. RNA sequencing (RNA-seq) analysis, Real-time PCR array, and western blotting were performed to explore possible signaling pathways involved in treatment of IF with hPMSCs. Results: hPMSC treatment can alleviate experimental hepatic fibrosis, restore liver function, and inhibit inflammation. Furthermore, the therapeutic effect of hPMSCs against mild to moderate LF was significantly greater than against severe disease. Mechanistic dissection studies suggested ameliorating LF using hPMSCs occur partly by restoring Caveolin-1 (Cav1) in activated hepatic stellate cells (HSCs). Upregulation of Cav1 can inhibit the TGF-β/Smad signaling pathway, mainly by reducing Smad2 phosphorylation, resulting in the inhibition of activated HSCs, whereas this effect could be abated if Cav1 was silenced in advance by siRNAs. Conclusions: Our findings suggest that hPMSCs could provide multifaceted therapeutic benefits for the treatment of LF, and the TGF-β/Cav1 pathway might act as a therapeutic target for hPMSCs in the treatment of LF.

Latency-associated Peptide Degradation Fragments Produced in Stellate Cells and Phagocytosed by Macrophages in Bile Duct-ligated Mouse Liver

2021 ◽  
pp. 002215542110536
Author(s):  
Ikuyo Inoue ◽  
Xian-Yang Qin ◽  
Takahiro Masaki ◽  
Yoshihiro Mezaki ◽  
Tomokazu Matsuura ◽  
...  
Keyword(s):  
Bile Duct ◽  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Mouse Liver ◽  
Transforming Growth Factor ◽  
Degradation Products ◽  
Stellate Cells ◽  
Transforming Growth Factor Β ◽  
Early Stages ◽  
Cell Source

Transforming growth factor-β (TGF-β) activation is involved in various pathogeneses, such as fibrosis and malignancy. We previously showed that TGF-β was activated by serine protease plasma kallikrein-dependent digestion of latency-associated peptides (LAPs) and developed a method to detect LAP degradation products (LAP-DPs) in the liver and blood using specific monoclonal antibodies. Clinical studies have revealed that blood LAP-DPs are formed in the early stages of liver fibrosis. This study aimed to identify the cell source of LAP-DP formation during liver fibrosis. The N-terminals of LAP-DPs ending at residue Arg58 (R58) were stained in liver sections of a bile duct-ligated liver fibrosis model at 3 and 13 days. R58 LAP-DPs were detected in quiescent hepatic stellate cells at day 3 and in macrophages on day 13 after ligation of the bile duct. We then performed a detailed analysis of the axial localization of R58 signals in a single macrophage, visualized the cell membrane with the anti-CLEC4F antibody, and found R58 LAP-DPs surrounded by the membrane in phagocytosed debris that appeared to be dead cells. These findings suggest that in the early stages of liver fibrosis, TGF-β is activated on the membrane of stellate cells, and then the cells are phagocytosed after cell death: (J Histochem Cytochem XX:XXX–XXX, XXXX)

Inhibition of hepatic stellate cells proliferation by mesenchymal stem cells and the possible mechanisms

2009 ◽  
Vol 39 (12) ◽  
pp. 1219-1228 ◽  
Author(s):  
Jing Wang ◽  
Chunjing Bian ◽  
Lianming Liao ◽  
Yashu Zhu ◽  
Jing Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Hepatic Stellate Cells ◽  
Stellate Cells

scholarly journals Suppression of transforming growth factor-β by mesenchymal stem-cells accelerates liver regeneration in liver fibrosis animal model

2021 ◽  
Vol 40 (1) ◽  
pp. 29
Author(s):  
Nur Anna C Sa’dyah ◽  
Agung Putra ◽  
Bayu Tirta Dirja ◽  
Nurul Hidayah ◽  
Salma Yasmine Azzahara ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Growth Factor ◽  
Liver Fibrosis ◽  
Transforming Growth Factor ◽  
Healing Process ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Significant Difference ◽  
T1 And T2

Introduction<br />Liver fibrosis (LF) results from the unregulated chronic wound healing process in liver tissue. Transforming growth factor-beta (TGF-β) is the major contributing cytokine of LF promotion through activation of quiescent hepatic stellate cells (HSCs) into myofibroblasts (MFs) and increased extracellular matrix (ECM) deposition such as collagen leading to scar tissue development. Mesenchymal stem cells (MSCs) have an immunomodulatory capability that could be used as a new treatment for repairing and regenerating LF through suppression of TGF-β. This study aimed to examine the role of MSCs in liver fibrosis animal models through suppression of TGF-β levels without scar formation particularly in the proliferation phase.<br /><br />Methods<br />In this study, a completely randomized design was used with sample size of 24. Male Sprague Dawley rats were injected intraperitoneally (IP) with carbon tetrachloride (CCl4), twice weekly, for eight weeks to induce LF. Rats were randomly assigned to four groups: negative control, CCl4 group, and CCL4 + MSC-treated groups T1 and T2, at doses of 1 x 106 and 2x106 cells, respectively. TGF-β levels were analyzed by enzyme-linked immunosorbent assay (ELISA). One-way ANOVA and a least significant difference (LSD) was used to analyse the data. <br /><br />Results<br />The TGF levels of LF rat models decreased on day 7 after MSC administration. The levels of TGF-β in both MSC groups T1 and T2 decreased significantly compared with the control group (p&lt;0.05). The TGF-β suppression capability of T2 was optimal and more significant than that of T1.<br /><br />Conclusion<br />MSCs can suppress TGF levels in liver fibrosis induced rats.

scholarly journals Human Menstrual Blood-Derived Stem Cells Ameliorate Liver Fibrosis in Mice by Targeting Hepatic Stellate Cells via Paracrine Mediators

2016 ◽  
Vol 6 (1) ◽  
pp. 272-284 ◽  
Author(s):  
Lijun Chen ◽  
Chunfeng Zhang ◽  
Lu Chen ◽  
Xiaojun Wang ◽  
Bingyu Xiang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Menstrual Blood
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