Purified hematopoietic stem cells can differentiate into hepatocytes in vivo

Abstract

The characterization of hepatic progenitor cells is of great scientific and clinical interest. Here we report that intravenous injection of adult bone marrow cells in the FAH(-/-) mouse, an animal model of tyrosinemia type I, rescued the mouse and restored the biochemical function of its liver. Moreover, within bone marrow, only rigorously purified hematopoietic stem cells gave rise to donor-derived hematopoietic and hepatic regeneration. This result seems to contradict the conventional assumptions of the germ layer origins of tissues such as the liver, and raises the question of whether the cells of the hematopoietic stem cell phenotype are pluripotent hematopoietic cells that retain the ability to transdifferentiate, or whether they are more primitive multipotent cells.

Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly

“…Considerable excitement and not a little controversy has been generated since the original 'proofof-concept' demonstration of the potential therapeutic utility of bone marrow to cure mice with the potentially fatal metabolic liver disease, hereditary tyrosinaemia type 1 [3]. The salient point to arise from this powerful demonstration of the therapeutic potential of bone marrow cells was that, although the initial engraftment was low (approximately one bone marrow cell for every million indigenous hepatocytes), the strong selection pressure exerted thereafter on the engrafted bone marrow cells resulted in their clonal expansion to eventually occupy almost half the liver.…”

“…More severe liver injury, particularly longstanding iterative injury (eg chronic viral hepatitis) or when replicative senescence ensues (eg steatohepatitis), activates a facultative stem cell compartment located within the intrahepatic biliary tree, giving rise to cords of bipotential transit amplifying cells (named oval cells in rodents and hepatic progenitor cells in man) that can ultimately differentiate into hepatocytes and biliary epithelial cells [2]. A third population of stem cells with hepatic potential resides in the bone marrow; these stem cells usually make little contribution to regeneration but, after fusing with metabolically defective hepatocytes, can be reprogrammed to contribute in a major way to restoring liver function [3][4][5]. Mesenchymal cells from bone marrow and other locations, particularly adipose tissue, appear to be the most suitable extra-hepatic candidate cells for hepatic differentiation.…”

Identification and Functional Characterization of Ion Channels in CD34+ Hematopoietic Stem Cells from Human Peripheral Blood

“…Despite the wellrecognized molecular phenotype of CD34 + HSCs, the regulatory mechanisms for proliferation and the molecular signals mediating mobilization, migration, and differentiation are only partially understood (Awong et al, 2009;Han et al, 2003;Nielsen and MaNagny, 2009;Steidl et al, 2002). Previous studies suggest that HSCs also are able to differentiate into nonhematopoietic cell types such as hepatocytes and cardiomyocytes (Lagasse et al, 2000;Orlic et al, 2001). Since CD34 + HSCs can be isolated from human peripheral blood, they have the potential to serve as therapeutic sources for a variety of degenerative diseases.…”

Characterization of two distinct liver progenitor cell subpopulations of hematopoietic and hepatic origins

“…Consistent with this premise, hematopoietic stem cells (HSCs) have been shown to transdifferentiate into cells of the hepatocytic lineage in both rodents and humans [16][17][18][19][20][21][22][23]. However, these findings have been challenged by studies showing that cell fusion rather than transdifferentiation of HSCs is involved in regeneration [24,25] and that bone marrow (BM) does not contribute as source of expanding oval cells [26].…”