Abstract
BackgroundLiver fibrosis is a major health problem worldwide and poses a serious obstacle for cell based therapies. Mesenchymal stem cells (MSCs) are multipotent and important candidate cells for future clinical applications however success of MSC therapy depends upon their homing and survival in recipient organs. This study was designed to improve the repair potential of MSCs by transplanting them in sodium nitroprusside (SNP) pretreated mice with CCl4 induced liver fibrosis.MethodsSNP 100 mM, a nitric oxide (NO) donor, was administered twice a week for 4 weeks to CCl4-injured mice. MSCs were isolated from C57BL/6 wild type mice and transplanted in the left lateral lobe of the liver in experimental animals. After 4 weeks, animals were sacrificed and liver improvement was analyzed. Analysis of fibrosis by qRT-PCR and sirius red staining, homing, bilirubin and alkaline phosphatase (ALP) serum levels between different treatment groups were compared to control.ResultsLiver histology demonstrated enhanced MSCs homing in SNP-MSCs group compared to MSCs group. The gene expression of fibrotic markers; αSMA, collagen 1α1, TIMP, NFκB and iNOS was down regulated while cytokeratin 18, albumin and eNOS was up-regulated in SNP-MSCs group. Combine treatment sequentially reduced fibrosis in SNP-MSCs treated liver compared to the other treatment groups. These results were also comparable with reduced serum levels of bilirubin and ALP observed in SNP-MSCs treated group.ConclusionThis study demonstrated that NO effectively augments MSC ability to repair liver fibrosis induced by CCl4 in mice and therefore is a better treatment regimen to reduce liver fibrosis.
Highlights
Liver fibrosis is a major health problem worldwide and poses a serious obstacle for cell based therapies
We observed a 3.0 fold increase in mRNA levels of α-smooth muscle actin (α-SMA) after treatment with CCl4 compared to 2.9 and 1.9 fold increase observed in Mesenchymal stem cells (MSCs) and sodium nitroprusside (SNP) treated groups
SNP-MSCs treatment resulted in only 1.6 fold increase in α-SMA which is significantly lower than other groups (Figure 1B)
Summary
Liver fibrosis is a major health problem worldwide and poses a serious obstacle for cell based therapies. Liver fibrosis is most often characterized by accumulation of wound healing myofibroblasts that replace normal hepatic tissue with scar at the site of injury [1,2]. Activated hepatic stellate cells (HSCs) produce high levels of extracellular matrix (ECM) proteins further contributing to scar development [3]. One of the hallmarks of liver injury is the development of scar tissue as a consequence of HSC activation. In response to liver injury, HSCs switch from quiescent vitamin A storing cells to proliferative, α smooth muscle actin expressing cells, up regulating synthesis of ECM proteins [11]. Prolonged injury results in failure to respond to negative feedback regulation of collagen synthesis and deposition of cross-linked type I collagen fibrils, which are resistant to proteolytic degradation leading to alteration of the normal liver ECM and change in organ architecture [14]
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