Impact of the KDR expressing hepatic progenitors in liver development
Our recent work published in Cell Stem Cell identified KDR (VEGFR2/FLK1) as a cell surface marker for a distinct conserved murine and human fetal liver progenitor. Small clusters of KDR+ fetal progenitors appear in the mouse foregut endoderm prior to the formation of hepatocyte progenitors, the hepatoblasts, defining them as upstream endodermal precursors for hepatoblasts. The unique property of the KDR+ progenitor is that it gives rise to not only a subset of fetal hepatoblasts (Cell Stem Cell, 2013) but also a subset of fetal endothelial cells (Stem Cell Reports, 2014). Our published data revealed thus that the fetal liver is composed of 2 distinct pools of hepatoblasts deriving either from KDR+ or KDR- endodermal progenitors, and 2 distinct pools of endothelial cells deriving either from KDR+ endodermal progenitors or mesodermal progenitors. We are currently investigating the distinct roles of the 2 pools of hepatobalsts and of endothelial cells in fetal liver organogenesis using lineage tracing mouse models as well as in vitro and in vivo functional assays.
Role of adult liver progenitor cells in liver regeneration
Liver transplantation is currently the only cure for acute and chronic liver failure, but the shortage of liver donors presents a critical challenge. A promising alternative solution to liver transplantation is the activation of existing and/or facultative liver progenitor cells (LPCs) in vivo. Although the liver has a robust ability to self-regenerate by proliferation of mature hepatocytes and cholangiocytes, in the case of acute or chronic liver injury, proliferation of mature cells is exhausted. Liver repair in most acute and chronic liver diseases in human is thus associated with expansion of LPCs in a process termed ductular reaction that is thought to contribute to liver regeneration. Several human liver diseases have been modeled in rodents, in which LPCs display progenitor features in vitro and to some extent a regenerative ability in vivo. These studies raise the exciting idea that forced activation of LPCs in sick livers will accelerate intrinsic liver regeneration. We are currently establishing tools to stimulate LPCs to promote liver repair.
Directed differentiation of human pluripotent stem cell (PSC) towards functional human hepatic cells for cell Therapy in liver diseases
The use of PSC differentiation cultures to generate functional hepatic cells for cell therapy of liver diseases is still an ongoing challenge. Even though a growing literature has established efficient protocols to generate such cells in vitro, PSC-derived hepatic cells remain inefficient at repopulating diseased livers. Our research is focused on identifying and modulating molecular pathways required for successful liver cell mass repopulation following hepatic cell transplantation into various liver deficient mouse models.