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

Abstract

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.

HLSC-Derived Extracellular Vesicles Attenuate Liver Fibrosis and Inflammation in a Murine Model of Non-alcoholic Steatohepatitis

“…MSC-derived EVs were able to reduce fibrosis in CCl4-and thioacetamide-induced chronic liver injures by alleviating hepatic inflammation and collagen deposition and by inhibiting epithelial-to-mesenchymal transition. [27][28][29][30] Moreover, EVs derived from serum reduced liver fibrosis in mice treated with CCl4 or thioacetic acid by improving liver function, reducing hepatocyte apoptosis, and suppressing inflammation. 31 These recent papers indicate that EVs can be exploited for therapy in liver diseases.…”

Embryotrophic effects of extracellular vesicles derived from outgrowth embryos in pre‐ and peri‐implantation embryonic development in mice

“…A communication between embryos and maternal uterine milieu through secreting signals is required for proper mammalian development (O'Neill, ). Recent studies observed that EVs are secreted from various somatic cells including human embryonic stem cell (Mardpour et al, ), induced pluripotent stem cell (Bobis‐Wozowicz et al, ), ovarian follicle (da Silveira et al, ), and even embryos (Qu et al, ). Our previous study also demonstrated that membrane budding microvesicles from outgrowth embryos improved developmental competence in vitro and the implantation potential of cocultured embryos in utero as well (Kim et al, ).…”

Dynamic Changes in Function and Proteomic Composition of Extracellular Vesicles from Hepatic Stellate Cells during Cellular Activation

“…HSC fibrogenesis is stimulated by these types of hepatocyte-derived EVs [29,32,41], while other phenotypic features of activated HSC such as migration and AKT phosphorylation have been shown to be enhanced by EVs from liver sinusoidal endothelial cells [42]. On the other hand, EVs from healthy hepatocytes [43], various stem cells [44][45][46][47][48][49][50][51] or the serum of healthy mice [52] have the ability to inhibit experimental liver fibrosis, largely by suppressing inflammatory responses and/or pathways of activation or fibrogenesis in HSC. The recognition that HSC are EV targets has highlighted an important new mechanism by which fibrogenic pathways in the liver are modulated and has given a new lead for novel anti-fibrotic therapies based on suppressing the action of pro-fibrotic EVs or harnessing the actions of EVs that are intrinsically anti-fibrotic.…”