MicroRNA125b-mediated Hedgehog signaling influences liver regeneration by chorionic plate-derived mesenchymal stem cells

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.

Exosomes as miRNA Carriers: Formation–Function–Future

“…Currently, exosomes from mesenchymal stem cells (MSCs) have attracted great attention worldwide and have been proposed as one of the most efficient liver cancer therapy options [42,43]. Research discoveries have shown that exosomes from MSCs exhibit potent protective activities towards liver diseases as observed in: promoting liver regeneration [44,45], suppressing the liver inflammatory response [46], alleviating liver fibrosis [44,47], increasing the sensitivity of liver cancer cells to chemotherapeutic agents [48], and promoting the anti-tumor activities of MSCs [49]. Besides, MSC-secreting exosomes, carrying miRNAs, reduce the growth [50] and suppress angiogenesis [51] of breast cancer cells.…”

Concise Review: Fetal Membranes in Regenerative Medicine: New Tricks from an Old Dog?

“…Similarly, hAEC have been exploited in a necroinflammatory carbon tetrachloride mouse model of liver fibrosis where intravenous hAEC administration reversed established liver fibrosis . This outcome was attributed to their polarization of macrophages from pro‐inflammatory M1 to pro‐regenerative M2 , as well as directly effects on hepatic stellate cells . In the setting of thioacetamide‐induced chronic liver failure, intrasplenically transplanted hAEC showed therapeutic efficacy while preserving HLA‐G expression .…”

Combatting Fibrosis: Exosome‐Based Therapies in the Regression of Liver Fibrosis

“…Exosomes are emerging as effective therapeutic tools for different diseases because these particles can bypass biological barriers and can serve as powerful drug and gene therapy transporters, raising the exciting prospect of “cell therapy without the cells.” The administration of MSC‐derived exosomes is a potential strategy for treating liver disease . The safety and feasibility observed in early clinical trials using MSCs has resulted in increased interest in the translation of the use of these cells to the clinic .…”