Hepatocyte growth factor/ c-met signaling is required for stem-cell–mediated liver regeneration in mice

Abstract

HGF/c-Met supports a pleiotrophic signal transduction pathway that controls stem cell homeostasis. Here, we directly addressed the role of c-Met in stem cell-mediated liver regeneration by utilizing mice harboring c-met floxed alleles and Alb-Cre or Mx1-Cre transgenes. To activate oval cells, the hepatic stem cell (HSC) progeny, we used a model of liver injury induced by diet containing the porphyrinogenic agent, 3, 5-diethocarbonyl-1,4-dihydrocollidine (DDC). Deletion of c-met in oval cells was confirmed in both models by PCR analysis of FACS- sorted EpCam-positive cells. Loss of c-Met receptor decreased sphere-forming capacity of oval cells in vitro as well as reduced oval cell pool, impaired migration and decreased hepatocytic differentiation in vivo as demonstrated by double immunofluorescence using oval- (A6 and EpCam) and hepatocyte-specific (HNF-4α) antibodies. Furthermore, lack of c-Met had a profound effect on tissue remodeling and overall composition of HSC niche which was associated with greatly reduced MMP9 activity and decreased expression of SDF1. Using a combination of double immunofluorescence of cell type-specific markers with MMP9 and gelatin zymography on the isolated cell populations, we identified macrophages as a major source of MMP9 in DDC-treated livers. The Mx1-Cre-driven c-met deletion caused the greatest phenotypic impact on HSCs response as compared to the selective inactivation in the epithelial cell lineages achieved in c-Metfl/fl; Alb-Cre+/- mice. However, in both models, genetic loss of c-met triggered a similar cascade of events leading to failure of HSCs mobilization and death of the mice. Conclusion: These results establish a direct contribution of c-Met in regulation of HSC response, and support a unique role for HGF/c-Met as an essential growth factor signaling pathway for regeneration of diseased liver.

FGF7 is a functional niche signal required for stimulation of adult liver progenitor cells that support liver regeneration

“…Thus, the role of FGF7 signal may be more direct and indispensable in LPC induction, while that of the Tweak/Fn14 pathway may be rather enhancing and not necessarily required. Recently, hepatocyte growth factor (HGF)/c-Met signaling has been reported to play a necessary role in LPC-mediated liver regeneration in the mouse DDC diet model (Ishikawa et al 2012), although it remains unexplored whether it can also be sufficient to induce the LPC response, as is the case with FGF7. The relationship between FGF7 and these signaling pathways is an important issue to be addressed.…”

“…À cells, which can be regarded as a fraction of newly formed hepatocytes (Engelhardt et al 1990;Ishikawa et al 2012), were clearly detected adjacent to A6 + CK19 + LPCs in FGF7 Tg mouse livers as well as in DDC-injured livers ( Fig. 5D; Supplemental Fig.…”

Biological roles of hepatocyte growth factor‑Met signaling from genetically modified animals (Review)

“…cKO mice treated with N-nitrosodiethylamine developed significantly more tumors of a larger size, associated with the increased proliferation and enhanced activation of estimated glomerular filtration rate signaling. Focusing on the oval cells (hepatic stem cell progeny), the liver-specific Met -/-mice were subjected to chronic liver injury, which was induced by a diet containing a porphyrinogenic agent (39).…”

“…The absence of Met caused severe hepatic degradation and prevented stem-cell-mediated liver regeneration; thus, HGF may also control liver regeneration via stem cells (39).…”

Specific fate decisions in adult hepatic progenitor cells driven by MET and EGFR signaling

“…Furthermore, using conditional liver-specific Met inactivation, we showed recently that progenitor-mediated regeneration is dependent on MET signaling. Adult HPCs defective in MET signaling failed to expand and could not commit to hepatocyte lineage in a model of chronic toxic liver injury (Ishikawa et al 2012).…”