A set of microRNAs mediate direct conversion of human umbilical cord lining-derived mesenchymal stem cells into hepatocytes

Abstract

In a previous study, we elucidated the specific microRNA (miRNA) profile of hepatic differentiation. In this study, we aimed to clarify the instructive role of six overexpressed miRNAs (miR-1246, miR-1290, miR-148a, miR-30a, miR-424 and miR-542-5p) during hepatic differentiation of human umbilical cord lining-derived mesenchymal stem cells (hMSCs) and to test whether overexpression of any of these miRNAs is sufficient to induce differentiation of the hMSCs into hepatocyte-like cells. Before hepatic differentiation, hMSCs were infected with a lentivirus containing a miRNA inhibitor sequence. We found that downregulation of any one of the six hepatic differentiation-specific miRNAs can inhibit HGF-induced hepatic differentiation including albumin expression and LDL uptake. Although overexpression of any one of the six miRNAs alone or liver-enriched miR-122 cannot initiate hepatic differentiation, ectopic overexpression of seven miRNAs (miR-1246, miR-1290, miR-148a, miR-30a, miR-424, miR-542-5p and miR-122) together can stimulate hMSC conversion into functionally mature induced hepatocytes (iHep). Additionally, after transplantation of the iHep cells into mice with CCL4-induced liver injury, we found that iHep not only can improve liver function but it also can restore injured livers. The findings from this study indicate that miRNAs have the capability of directly converting hMSCs to a hepatocyte phenotype in vitro.

MiR‐30a attenuates immunosuppressive functions of IL‐1β‐elicited mesenchymal stem cells via targeting TAB3

“…The up-regulation of miR-30a was observed in decidua-derived MSCs from patients with severe PE through miRNA chip data [25], and its impacts on carcinogenesis were also investigated [27][28][29][30]. Additionally, miR-30a was revealed to participate in the osteoblastic and osteocytic differentiation of MSCs [31,32]. However, the exact mechanisms by which miR-30a manipulates the immunomodulatory function of MSCs and subsequently the pathogenesis of PE have not yet been clarified.…”

The combination of miR‐122 overexpression and Let‐7f silencing induces hepatic differentiation of adipose tissue‐derived stem cells

“…Notably, several miRNAs have been recently reported to be involved in hepatic differentiation of stem cells suggesting their critical role in differentiation induction (Cui et al, 2013;Davoodian et al, 2014b;Jung et al, 2016). Notably, several miRNAs have been recently reported to be involved in hepatic differentiation of stem cells suggesting their critical role in differentiation induction (Cui et al, 2013;Davoodian et al, 2014b;Jung et al, 2016).…”

Noncoding RNAs and Their Potential Therapeutic Applications in Tissue Engineering

“…Using a set of miRNAs instead of a single miRNA is another approach to optimize hepatic differentiation. Overexpression of seven miRNAs (miR-1246, miR-1290, miR-148a, miR-30a, miR-424, miR-542-5p, and miR-122) induced human MSC (hMSC) conversion into functionally mature hepatocytes, while a single miRNA could not initiate hepatic differentiation [65].…”