ABSTRACT
Liver progenitor cells (LPCs) have a remarkable contribution to the hepatocytes and ductal cells when normal hepatocyte proliferation is severely impaired. As a biomarker for LPCs, Sry-box 9 (Sox9) plays critical roles in liver homeostasis and repair in response to injury. However, the regulation mechanism of Sox9 in liver physiological and pathological state remains unknown. In this study, we found that miR-126 positively regulated the expression of Sox9, the proliferation and differentiation of SOX9+ LPCs by suppressing the translation of homeobox b6 (Hoxb6). As a transcription factor, HOXB6 directly binds to the promoter of Sox9 to inhibit Sox9 expression, resulting in the destruction of the properties of SOX9+ LPCs in CCl4-induced liver injury. These findings revealed the role of miR-126 in regulating SOX9+ LPCs fate by targeting Hoxb6 in liver injury repair. Our findings suggest the potential role of miR-126 as a nucleic acid therapy drug target for liver failure.
Subject(s)
Homeodomain Proteins/metabolism , Liver Regeneration , Liver/metabolism , MicroRNAs/metabolism , SOX9 Transcription Factor/metabolism , Stem Cells/metabolism , Animals , Base Sequence , Carbon Tetrachloride , Cell Differentiation/genetics , Cell Line, Tumor , Cell Proliferation/genetics , Chronic Disease , Dependovirus/metabolism , Disease Models, Animal , Hepatocytes/cytology , Liver/injuries , Liver/physiopathology , Male , Mice , Mice, Inbred C57BL , NIH 3T3 CellsABSTRACT
Liver regeneration/repair is a compensatory regrowth following acute liver failure, and bone marrow-derived mesenchyme stem cell (BMSC) transplantation is an effective therapy that promotes liver regeneration/repair. Wnt1 inducible signaling pathway protein 2 (Wisp2) is highly expressed in BMSCs, however, its function remains unclear. In this work, we used clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein -9 nuclease (CRISPR/Cas9) genome editing technology to knockdown Wisp2 in BMSCs, and these modified cells were then transplanted into rats which were induced by the 2-AAF/PH. By linking the expression of Cas9 to green fluorescent protein (GFP), we tracked BMSCs in the rats. Disruption of Wisp2 inhibited the homing of BMSCs to injured liver and aggravated liver damage as indicated by remarkably high levels of ALT and AST. Moreover, the key factor in BMSC transplantation, C-X-C chemokine receptor type 4 (Cxcr4), was down-regulated in the Wisp2 depleted BMSCs and had a lower expression in the livers of the corresponding rats. By tracing the GFP marker, more BMSCs were observed to differentiate into CD31 positive endothelial cells in the functional Wisp2 cells but less in the Wisp2 gene disrupted cells. In summary, Wisp2 promotes the homing of BMSCs through Cxcr4 related signaling during liver repair in rats.
