Extracellular vesicles derived from human embryonic stem cell‐MSCs ameliorate cirrhosis in thioacetamide‐induced chronic liver injury

Various somatic tissue‐derived mesenchymal stromal cells (MSCs) have been considered as an attractive therapeutic tool for treatment of liver diseases in which the secretion of soluble factors or extracellular vesicles (EVs) is the most probable mechanism. The experimental application of human embryonic stem cell‐derived MSC (ES‐MSC) increased rapidly and showed promising results, in vitro and in vivo. However, possible therapeutic effects of human ES‐MSC and their EVs on Thioacetamide (TAA)‐induced chronic liver injury have not been evaluated yet. Our data indicated that human ES‐MSC can significantly suppress the proliferation of peripheral blood mononuclear cells compared to bone marrow (BM)‐MSC and adipose (AD)‐MSC. Moreover, ES‐MSC increased the secretion of anti‐inflammatory cytokines (i.e., TGF‐β and IL‐10) and decreased IFN‐γ, compared to other MSCs. ES‐MSC EVs demonstrated immunomodulatory activities comparable to parental cells and ameliorated cirrhosis in TAA‐induced chronic rat liver injury, that is, reduction in fibrosis and collagen density, necrosis, caspase density, portal vein diameter, and transaminitis. The gene expression analyses also showed upregulation in collagenases (MMP9 and MMP13), anti‐apoptotic gene (BCL‐2) and anti‐inflammatory cytokines (TGF‐β1 and IL‐10) and down‐regulation of major contributors to fibrosis (Col1α, αSMA, and TIMP1), pro‐apoptotic gene (BAX) and pro‐inflammatory cytokines (TNFα and IL‐2) following treatment with ES‐MSC and ES‐MSC‐EV. These results demonstrated that human ES‐MSC and ES‐MSC EV as an off‐the‐shelf product, that needs further assessment to be suggested as an allogeneic product for therapeutic applications for liver fibrosis. In present study, we found the superiority of ES‐MSC and ES‐MSC EVs regarding immunomodulatory potential in comparison to those from BM‐ and AD‐MSCs through the secretion of anti‐inflammatory cytokines in vitro. ES‐MSCs and ES‐MSC EVs also offer anti‐fibrotic, anti‐necrotic and immunosuppressive effects to modulate TAA‐induced cirrhotic livers after successfully engraftment in recipient damaged livers. To our knowledge, this is the preliminary evidence explaining hepatoprotective effects of ES‐MSCs and their EVs in chronic liver disease model.