Abstract
Although chorionic plate-derived mesenchymal stem cells (CP-MSCs) were shown to promote liver regeneration, the mechanisms underlying the effect remain unclear. Hedgehog (Hh) signaling orchestrates tissue reconstruction in damaged liver. MSCs release microRNAs mediating various cellular responses. Hence, we hypothesized that microRNAs from CP-MSCs regulated Hh signaling, which influenced liver regeneration. Livers were obtained from carbon tetrachloride (CCl4)-treated rats transplanted with human CP-MSCs (Tx) or saline (non-Tx). Sonic Hh, one of Hh ligands, increased in CCl4-treated liver, whereas it decreased in CP-MSC-treated liver with CCl4. The expression of Hh-target genes was significantly downregulated in the Tx. Reduced expansion of progenitors and regressed fibrosis were observed in the liver of the Tx rats. CP-MSCs suppressed the expression of Hh and profibrotic genes in co-cultured LX2 (human hepatic stellate cell) with CP-MSCs. MicroRNA-125b targeting smo was retained in exosomes of CP-MSCs. CP-MSCs with microRNA-125b inhibitor failed to attenuate the expression of Hh signaling and profibrotic genes in the activated HSCs. Therefore, these results demonstrated that microRNA-125b from CP-MSCs suppressed the activation of Hh signaling, which promoted the reduced fibrosis, suggesting that microRNA-mediated regulation of Hh signaling contributed to liver regeneration by CP-MSCs.
Highlights
Liver disease is one of the most common diseases worldwide
Indian Hh (Ihh)-positive cells in the liver from the Tx rats were predominantly located in the portal tract areas and expressed by hepatic stellate cells (HSCs) and oval-looking cells but not hepatocytic cells (Fig. 1C,D, Supplementary Fig. S1), whereas these cells were rarely detected in the livers from the non-Tx rats
These results indicate that Sonic Hh (Shh) and Ihh might have distinct effects on chorionic plate-derived mesenchymal stem cells (CP-Mesenchymal stem cells (MSCs))-mediated liver regeneration
Summary
Liver disease is one of the most common diseases worldwide. Mild liver disease can be cured by appropriate treatments. Express stem cell markers (Oct-4, Nanog, Sox[2], and TERT), germ layer markers (NF68, cardiac muscle, α -fectoprotein) and an immunomodulator gene (HLA-G)[6] They share common characteristics with BM-MSCs and have several advantages, such as mutipotency, easy accessibility, abundance, and immunosuppressive characteristics[6,7]. In the injured liver, dying hepatocytes were shown to release Hh ligands[19,20] These Hh ligands trigger the proliferation of Hh-responsive cells, such as hepatic progenitor cells and hepatic stellate cells (HSCs), which produce Hh ligands and amplify the activity of Hh signaling in those cells in an autocrine and paracrine manner[18,19,20,21]. These findings demonstrate that Hh signaling is critically important in hepatic fibrogenesis
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