Nitric oxide augments mesenchymal stem cell ability to repair liver fibrosis

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.

Mesenchymal Stem/Stromal Cells in Liver Fibrosis: Recent Findings, Old/New Caveats and Future Perspectives

“…Ali et al [117] showed that when a mouse model of carbon tetrachloride (CCl4) was treated with sodium nitroprusside (SNP) before MSCs transplantation, liver fibrosis was further ameliorated when compared to control MSCstreated group suggesting a positive role of nitric oxide. Interestingly, pre-incubation of MSCs with interferongamma (INF-γ) was shown to induce the expression of well known immunomodulatory factors such as indoleamine 2,3-dioxygenase (IDO), HGF and cyclooxygenase-2 (COX-2), likely playing a role in liver fibrosis amelioration mediated by MSCs [114].…”

Bone Marrow-Derived Mesenchymal Stem Cells Promote Hepatic Regeneration after Partial Hepatectomy in Rats

“…The treatment of BM-MSCs after 70% hepatectomy might face a similar problem. However, administration of a growth factor or nitric oxide donor, such as insulin-like growth factor 1 [30] and sodium nitroprusside [31], to increase the differentiation and repair ability of BM-MSCs after transplantation might overcome this problem. Therefore, using progenitor cells which could migrate and differentiate into hepatocytes at the liver might be an alternative strategy for the treatment of liver injury.…”

Nitric Oxide Activates Signaling by c-Raf, MEK, p-JNK, p38 MAPK and p53 in Human Mesenchymal Stromal Cells inhibits their Osteogenic Differentiation by Blocking Expression of Runx2

“…However, the regulation of Runx2 is complex and both activatory and inhibitory effects were observed, depending on the experimental set-up [71,76] (Figure 5). In contrast, low doses of NO may facilitate osteogenic differentiation or NO facilitated MSC-mediated tissue repair in vivo [77,78]. Low NO thus may be beneficial to patients suffering from osteoporosis or bone defects.…”