Matrix Metalloproteinase-14 controls differentiation of fetal hepatic stem/progenitor cells

Matrix Metalloproteinase (MMP)-14 is a representative of membrane-type MMP. MMP-14 regulates the motility of hematopoietic and mesenchymal stem cells, however, the pathological and physiological functions of MMP-14 in hepatic stem/progenitor cells (HSPC) are unknown. The objective of this study is to clarify the function of MMP-14 in the differentiation of HSPC.
To investigate the function of MMP-14 in the differentiation of HSPC, we analyzed the phenotype of mid-gestational Dlk⁺ HSPC using tetracycline-inducible lentiviral overexpression of MMP-14 and MMP-2, and those derived from systemic MMP-14 deficient mice. We analyzed the expression profile of MMP-14 deficient livers using cDNA microarray.
In vitro differentiation assays showed that overexpression of MMP-14 increased the number and size of bile-duct like colonies derived from primary wild-type HSPC, and promoted the expression of HNF1β, Notch-1, Jagged-1, and Hes1, whereas overexpression of MMP-2 did not change biliary differentiation of such cells. In contrast, the formation of bile-duct like colonies derived from MMP-14 deficient HSPC was completely impaired. Microarray analysis of MMP-14 deficient neonatal livers showed the increased expression of molecules associated with metabolic functions in hepatocytes and decreased expression of those with biliary markers, including Cytokeratin-19 and Notch-Delta pathway, as compared with littermate wild-type livers.
These data suggest that MMP-14 positively regulates the differentiation of fetal hepatic stem/progenitor cells.