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.
Highlights
Liver cancer is one of the most frequently diagnosed cancers worldwide and one of the leading causes of cancer death
We used clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein -9 nuclease (CRISPR/Cas9) genome editing technology to knockdown Wnt1 inducible signaling pathway protein 2 (Wisp2) in bone marrow-derived mesenchyme stem cell (BMSC), and these modified cells were transplanted into rats which were induced by the 2-AAF/PH
Wisp2 has been reported to be expressed in BMSCs, to explore the function of Wisp2, we detected its expression by PCR and western blot
Summary
Liver cancer is one of the most frequently diagnosed cancers worldwide and one of the leading causes of cancer death. An estimated 782,500 new liver cancer cases and 745,500 deaths occurred worldwide in 2012. Half of these cases and deaths were estimated to occur in China [1, 2]. Acute liver injury (ALI) and acute liver failure (ALF) are syndromes characterized by a rapid loss of functional hepatocytes in patients with no evidence of pre-existing liver disease. Many patients with ALF deteriorate severely, and liver transplantation remains their only option for survival [3]. Because of the limited donor availability, attention has been focused on the possibility of restoring liver mass and function through cell transplantation [4]. Bone marrow cells can be considered a pool from which exogenous cells www.impactjournals.com/oncotarget could be derived for liver regeneration/repair [5], and among those cells, bone marrow-derived mesenchyme stem cells (BMSCs) have the most potential [6]
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