Transplantation of human matrix metalloproteinase-1 gene-modified bone marrow-derived mesenchymal stem cell attenuates CCL4-induced liver fibrosis in rats

Abstract

Abstract. It has been reported that bone marrow-derived mesenchymal stem cells (BMSCs) alleviated liver fibrosis. We investigated whether BMSCs transfected with human matrix metalloproteinase 1 (BMSCs/MMP1) would improve their therapeutic effect in liver fibrosis induced by carbon tetrachloride (CCl 4 ) in rats. BMSCs were transfected with an adenovirus carrying enhanced green fluorescence protein (GFP) and human MMP1 gene. BMSCs or BMSCs/MMP1 were directly injected into fibrotic rats via the tail vein. GFP-labeled cells appeared in the fibrotic liver after BMSC transplantation. The expression of BMSCs/MMP1 elevated levels of MMP1 in vitro. Although BMSC administration reduced liver fibrosis, transplantation of BMSCs/MMP1 enhanced the reduction of liver fibrosis to a higher level. Treatment with BMSCs/MMP1 not only decreased collagen content but also suppressed activation of hepatic stellate cells (HSCs) in fibrotic liver, which led to subsequent improvement of both liver injury and fibrosis. Treatment with BMSCs/MMP1 resulted in an improved therapeutic effect compared with BMSCs alone, which is probably because of the sustainably expressed MMP1 level in the liver. BMSCs/MMP1 transplantation not only improved biochemical parameters but also attenuated progression of liver fibrosis, suggesting that BMSCs may be a potential cell source in preventing liver fibrosis and MMP1 gene may enhance the anti-fibrotic effect of BMSCs.

Reversal of established liver fibrosis by IC-2-engineered mesenchymal stem cell sheets

“…These results suggest that the fibrolytic activity of IC-2 sheets on liver fibrosis is dependent on MMP-14. Although MMP-1 possesses potent collagenolytic activity 42 , the fibrinolytic effect of si-MMP-1-transfected IC-2 sheets was marginal. To assess the expression of these MMPs in cell sheets over time, MMP-1 and MMP-14 levels were determined in liver tissues containing cell sheets by reverse-transcription polymerase chain reaction (RT-PCR) analysis using human-specific primers (Fig.…”

Strategies to improve the efficiency of mesenchymal stem cell transplantation for reversal of liver fibrosis

“…66 In addition, MSCs transfected with MMP-1 enhanced the reduction of liver fibrosis than MSC group by downregulating collagen content and inhibiting activation of HSCs. 67 Overexpression of IGF-I in MSCs significantly increased the levels of IGF-I and HGF in the livers of treated mice than MSC group, and multiple doses of modified MSCs dramatically suppressed inflammatory responses and reduced collagen deposition in fibrotic livers. 68 Overexpression of HGF in MSCs also enhances the migratory ability of MSCs, and these modified MSCs have stronger responses to SDF-1α than control MSCs.…”

Immunity-and-matrix-regulatory cells derived from human embryonic stem cells safely and effectively treat mouse lung injury and fibrosis

“…It has been reported that transplantation of human MMP1overexpressing bone marrow-derived mesenchymal stem cells can attenuate CCL4-induced liver fibrosis in rats. 27 Therefore, it is conceivable that IMRCs that highly express MMP1 may also reverse lung fibrosis. Accordingly, our data showed that the secretomes from IMRCs could reduce collagen I levels during fibrogenesis induced by TGF-β1.…”

“…Although fibroblastic foci, alveolar epithelial type 2 cells hyperplasia and honeycombing lesions are reduced compared with those in humans, indicating that the modeling of human ARDS is not complete in the mouse BLM model, injury to alveolar epithelial cells has been shown to be a common contributing factor to the pathogenesis of both human ARDS and BLM-induced mouse pulmonary injury. 27,28 To test the therapeutic efficacy of IMRCs in the BLM mouse model, the delivery route and schedule of administration (e.g., single dose vs repeated doses) were carefully considered. Intravenous infusion is one of the principal delivery routes, considered to be minimally invasive, simple to use, and is the most common mode for primary MSCs delivery in diverse lung disorders.…”