Wisp2 disruption represses Cxcr4 expression and inhibits BMSCs homing to injured liver

Abstract

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.

Expression and biological function of the cellular communication network factor 5 (CCN5) in primary liver cells

“…CCN5 expression is lowered in HCC tumor tissues compared with normal tissue, while contrarily high CCN5 expression was associated with better prognosis in HCC, suggesting a dual role in CCN5 activity (Jia et al 2021). Possibly, these beneficial effects might be related to the fact that CCN5 promotes the homing of bone marrow‐derived mesenchymal stem cells, which promote liver regeneration and repair (Qin et al 2017). However, the precise biological function of CCN5 in the different liver cell types, liver homeostasis, and hepatic injury are still unknown.…”

“…In contrast, high expression of CCN5 in vivo provokes enhanced infiltration of fibroblasts by triggering the expression of HMGB1 that weakens the anticancer effects (Jia et al 2021). In addition, CCN5 promotes liver repair by stimulating the in vivo homing of bone mesenchymal stem cells to the injured liver and stimulating endothelial cell proliferation and angiogenesis through modulating Cxcr4 signaling (Qin et al 2017).…”