[Which stem cells for adult liver?]

Abstract

While hepatocytes can be considered conceptually as unipotent stem cells, the presence of true stem or progenitor cells within adult livers has been largely debated. It is now accepted that the atypical ductular reaction observed in livers with sub-massive hepatitis represents the proliferation of hepatic progenitor cells similar to rat oval cells and able to differentiate towards the biliary and the hepatocytic lineage through intermediate progeny. In the normal liver, the identification of progenitor cells with a panel of markers including c-kit, CD34, Ov6, CK7, CK19, chromogranine A, CD56 remains difficult because these cells are very few and most of the markers are not specific. These progenitor cells could be located either within the canals of Hering or in periductular situation or both. Mechanisms leading to the activation and the proliferation of hepatic progenitor cells are still largely unknown: they involve growth factors as the stem cell factor, ligand of c-kit, cytokines, chemokines as SDF1 a and vagal or sympathetic innervatioñ. Other potential stem cells for liver could be hematopoietic stem cells from bone marrow. First publications have showed that hematopoietic stem cells were able to differentiate into hepatocytes and cholangiocytes and to yield high level engraftment of injured livers. However it appears now that this phenomenon is minimal or even absent in physiological and usual pathological conditions. It does occur in extreme experimental conditions either by true transdifferentiation or cell fusion. The shared property of stem cells and tumor cells to proliferate endlessly, rises the question of the potential role of progenitor cells in liver carcinogenesis. In a number of animal models of hepatocarcinogenesis, tumors originate from oval cells. The identification of progenitor cells close to murine oval cells in the human liver raises the hypothesis of a potential role of these cells in the development of human liver tumors. Liver progenitor cells have been identified morphologically and phenotypically in dysplastic foci of cirrhotic livers and hepatocellular adenomas. More generally speaking, typical hepatocellular carcinomas and cholangiocarcinomas are at the two ends of a spectrum which includes transitional-type tumors intermediate between hepatocellular carcinoma and cholangiocarcinoma and combined hepato-cellular cholangiocarcinoma; these intermediate and combined types can be more easily explained as deriving from progenitor cells. Despite the difficulties, the doubts and the potential dangers, new experimental modalities to obtain efficient repopulation of the liver from bone marrow stem cells are currently under study: exogenous administration of cytokines and chemokines involved in cell homing and differentiation or development of selective pressure strategies. Other cell types as intra-hepatic progenitor cells, bone marrow multipotent adult progenitor cells (MAPCs) or fetal hepatocytes could be alternative sources for liver cell therapy. Thus, progressing knowledge about stem cells in adult liver would allow to better understand mechanisms of hepatic homeostasia and regeneration and would open the way to cell-based therapy for liver diseases.