Extracellular Vesicles Secreted by Human Adipose-derived Stem Cells (hASCs) Improve Survival Rate of Rats with Acute Liver Failure by Releasing lncRNA H19

Hepatocyte transplantation utilizing induced pluripotent stem cells (iPSCs) or embryonic stem cells (ESCs) has been expected to provide an alternative to liver transplantation. However, it remains uncertain precisely which cell type is the best suited for cell transplantation. In particular, it is unclear whether mature hepatocytes, which have sufficient liver function, or immature hepatic progenitor cells, which have a higher proliferative capacity, will provide a better outcome. The main objective of this study was to investigate the therapeutic efficacy of the transplantation of hepatocytes at various differentiation stages. We utilized transgenic mice that expressed diphtheria toxin (DT) receptors under the control of an albumin enhancer/promoter. ESC-derived endodermal cells, fetal hepatocytes, and adult hepatocytes were transplanted into these mice with experimentally induced lethal acute liver injury caused by DT administration. The transplanted cells were marked by enhanced green fluorescent protein. We evaluated their effects on survival. At 35 days after transplantation, the survival rate of the adult hepatocyte-transplanted group (8/20, 40%) was significantly improved in comparison to that of the sham-operated group (2/25, 8%), the fetal hepatocyte-transplanted group (1/20, 5%), and the ESC-derived endodermal cell-transplanted group (0/21, 0%). The adult hepatocytes proliferated in the recipient livers and replaced a large part of their parenchyma. The transplantation of adult hepatocytes for acute liver failure significantly improved the survival rate in comparison to that of transplantation of immature cells, thus suggesting that ESCs and iPSCs should be differentiated into mature hepatocytes before cell transplantation for acute liver failure.

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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

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/4253846 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13

Author(s):

Lu Wang ◽

Shu Li ◽

Han-Yu Wang ◽

Juan Zeng ◽

Zheng-Zheng Zhang ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Survival Rate ◽

Growth Factor ◽

Hepatocyte Growth Factor ◽

Liver Failure ◽

Acute Liver Failure ◽

Therapeutic Effect ◽

Factor C ◽

Hepatocyte Growth

Acute liver failure (ALF) is a serious life-threatening condition. Mesenchymal stem cells (MSCs) may be an effective treatment for this condition and a good alternative to liver transplantation. Icaritin (ICT) is an active ingredient of the genus Epimedium, a traditional Chinese medicine, with the potential to enhance the proliferation of MSCs. The purpose of this study was to explore whether ICT increased the therapeutic effects of MSCs and explore its underlying mechanisms. For in vivo experiments, a rat ALF model was established by intraperitoneal injection of D(+)-galactosamine/ lipopolysaccharide. MSCs cocultured with ICT were used to treat ALF rats and the protective effects assessed as survival rate, levels of serum AST and ALT, and histological changes in liver tissue. For in vitro experiments, MSCs were treated in serum-free culture for 72 h to simulate the disruption of intrahepatic microcirculation. MSCs apoptosis was examined to determine whether ICT rescued impaired MSCs. The role of the hepatocyte growth factor (HGF)/c-Met pathway in MSCs was assessed by constructing genetically modified MSCs overexpressing c-Met and by using the c-Met receptor inhibitor (crizotinib). The results showed that MSCs increased the survival rate of ALF rats and reduced liver damage. MSCs cocultured with ICT exerted a greater therapeutic effect than MSCs alone. Further, the HGF/c-Met pathway played a key role in the antiapoptotic activity of MSCs, which was associated with the optimized efficacy of ICT. In conclusion, this study demonstrated that ICT enhances the therapeutic effect of MSCs in a model of ALF, improving the antiapoptotic potential of MSCs by upregulation of the HGF/c-Met pathway. The combination of stem cell therapy with traditional herbal extracts may improve MSC-based clinical applications.

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Small Extracellular Vesicles From Human Adipose-derived Stem Cells: A Potential Promoter of Keeping Fat Graft Survival

10.21203/rs.3.rs-127314/v1 ◽

2020 ◽

Author(s):

Aizhen Chen ◽

Shijie Tang ◽

Jiawei He ◽

Xiangyu Li ◽

Guohao Peng ◽

...

Keyword(s):

Stem Cells ◽

Survival Rate ◽

Regenerative Medicine ◽

Extracellular Vesicles ◽

Umbilical Vein ◽

Fat Graft ◽

Control Group ◽

Adipose Derived Stem Cells ◽

Ki 67

Abstract Background: Small extracellular vesicles (sEVs) with genetic information secreted by cells play a crucial role in the cellular microenvironment. In this study, our purpose is to explore the characteristics of the small extracellular vesicles of human adipose-derived stem cells (hADSC-sEVs) and studied the role of hADSC-sEVs in improving the survival rate of grafted fat.Methods: In the present study, we used the transmission electron microscopy, nano-tracking analysis, nanoflow surface protein analysis, zeta potential value to identify sEVs. SEVs' trajectory was traced dynamically to verify whether hADSC-sEVs can be internalized into human umbilical vein endothelial cells (HUVECs) in vitro. The angiogenic property of hADSC-sEVs was observed by measuring the volume, weight and histological analysis of the grafted fats in nude mice modles. Results: Our research showed that the extracellular vesicles were sEVs with double-layer membrane structure and the diameter of which is within 30-150nm. hADSC-sEVs exert biological influence mainly through internalization into cells. Compared with the control group, the hADSC-sEVs group had a significantly higher survival rate of grafted fat, morphological integrity and a lower degree of inflammation and fibrosis. And immunohistochemistry showed that hADSC-sEVs significantly increased the neovascularisation and the expression of CD34, VEGFR2 and KI-67 in the graft tissue. Conclusions: As a potential nanomaterial, hADSC-sEVs has been explored in the field of cell-free application of stem cell technology. hADSC-sEVs promoted the survival of grafted fats by promoting the formation of new blood vessels, which is another promising progress in the field of regenerative medicine. We believe that hADSC-sEVs will have a broad application prospect in the field of regenerative medicine in the future.

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