Secreted matrix metalloproteinase-14 is a predictor for antifibrotic effect of IC-2-engineered mesenchymal stem cell sheets on liver fibrosis in mice

Abstract

Introduction Transplantation of IC-2-engineered bone marrow-derived mesenchymal stem cell (BM-MSC) sheets (IC-2 sheets) was previously reported to potentially reduce liver fibrosis. Methods This study prepared IC-2-engineered cell sheets from multiple lots of BM-MSCs and examined the therapeutic effects of these cell sheets on liver fibrosis induced by carbon tetrachloride in mice. The predictive factors for antifibrotic effect on liver fibrosis were tried to identify in advance. Results Secreted matrix metalloproteinase (MMP)-14 was found to be a useful predictive factor to reduce liver fibrosis. Moreover, the cutoff index of MMP-14 for 30% reduction of liver fibrosis was 0.918 fg/cell, judging from univariate analysis and receiver operating curve analysis. In addition, MMP-13 activity and thioredoxin contents in IC-2 sheets were also inversely correlated with hepatic hydroxyproline contents. Finally, IC-2 was also found to promote MMP-14 secretion from BM-MSCs of elderly patients. Surprisingly, the values of secreted MMP-14 from BM-MSCs of elderly patients were much higher than those of young persons. Conclusion The results of this study suggest that the IC-2 sheets would be applicable to clinical use in autologous transplantation for patients with cirrhosis regardless of the patient's age.

Extracellular Matrix Synthesis and Remodeling by Mesenchymal Stromal Cells Is Context-Sensitive

“…Rather, the MMP found in the supernatants were in the molecular weight range of gelatinases (such as MMP2 and MMP9) and membrane-type MMP (such as MMP14 and others), with differences between groups observed mainly in the weight range of the membrane-type MMP. This was interesting as recently, it was demonstrated that secreted MMP14 is a suitable predictor for MSC potency to reduce liver fibrosis [31]. Considering this, reduced MMP14 secretion and activation would represent a maladaptation of MSC in fibrotic environment, which may have to be addressed when attempting MSC-based therapies of ECM disease.…”

Intestinal Fibrosis in Inflammatory Bowel Disease and the Prospects of Mesenchymal Stem Cell Therapy

“…Engineered MSC possesses an enhanced regulatory effect in inhibiting and reversing liver fibrosis. IC-2 engineered BM-MSC was proven to have the potential to relieve liver fibrosis (190). Just as indicated earlier, MSCs functionally alleviate liver fibrosis by producing cytokines or factors, directly acting on target cells, and secreting EVs.…”