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

J Cell Physiol. 2018 Dec;233(12):9330-9344. doi: 10.1002/jcp.26413. Epub 2018 Jun 19.


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.

Keywords: cirrhosis; extracellular vesicles; human embryonic stem cells; liver; mesenchymal stromal cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / cytology
  • Animals
  • Apoptosis
  • Bone Marrow Cells / cytology
  • Cell Line
  • Cell Survival
  • Chronic Disease
  • Cytokines / metabolism
  • Disease Models, Animal
  • Extracellular Vesicles / metabolism*
  • Extracellular Vesicles / ultrastructure
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Human Embryonic Stem Cells / cytology
  • Human Embryonic Stem Cells / metabolism*
  • Humans
  • Immunomodulation
  • Liver / injuries*
  • Liver / pathology
  • Liver Cirrhosis / pathology
  • Liver Cirrhosis / therapy*
  • Male
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / metabolism*
  • Rats, Wistar
  • Thioacetamide


  • Cytokines
  • Thioacetamide