Clonal identification and characterization of self-renewing pluripotent stem cells in the developing liver

TLDR

Manipulation of hepatic stem cells may provide new insight into therapies for diseases of the digestive system. Using flow cytometry and single‑cell assays, we prospectively identified hepatic stem cells with multilineage differentiation potential and self‑renewing capability. Clonally expanded hepatic stem cells continuously produced hepatocytes and cholangiocytes, maintained self‑renewal, and when transplanted into mice differentiated into liver, bile duct, pancreatic, and intestinal cells, demonstrating that self‑renewing pluripotent stem cells persist in the developing mouse liver and can generate multiple endodermal lineages under suitable microenvironments.

Abstract

Using flow cytometry and single cell–based assays, we prospectively identified hepatic stem cells with multilineage differentiation potential and self-renewing capability. These cells could be clonally propagated in culture where they continuously produced hepatocytes and cholangiocytes as descendants while maintaining primitive stem cells. When cells that expanded in vitro were transplanted into recipient animals, they morphologically and functionally differentiated into hepatocytes and cholangiocytes with reconstitution of hepatocyte and bile duct structures. Furthermore, these cells differentiated into pancreatic ductal and acinar cells or intestinal epithelial cells when transplanted into pancreas or duodenal wall. These data indicate that self-renewing pluripotent stem cells persist in the developing mouse liver and that such cells can be induced to become cells of other organs of endodermal origin under appropriate microenvironment. Manipulation of hepatic stem cells may provide new insight into therapies for diseases of the digestive system.