Albumin-expressing hepatocyte-like cells develop in the livers of immune-deficient mice that received transplants of highly purified human hematopoietic stem cells

Abstract

Rodent bone marrow cells can contribute to liver. If these findings are applicable to humans, marrow stem cells could theoretically be harvested from a patient and used to repair his/her damaged liver. To explore this potential, CD34(+) or highly purified CD34(+)CD38(-)CD7(-) human hematopoietic stem cells from umbilical cord blood and bone marrow were transplanted into immunodeficient mice. One month after transplantation, carbon tetrachloride (CCl(4)) was administered into the mice to induce liver damage and hepatocyte proliferation. Mice were analyzed in comparison with CCl(4)-injured mice that did not receive transplants and noninjured controls that received transplants with the same stem cell populations, one month after liver damage. Human-specific albumin mRNA and protein were expressed in the mouse liver and human albumin was detected in the serum of mice that had received CCl(4) injury. Human alpha-fetoprotein was never expressed, but in some mice, human cytokeratin 19 was expressed, which may indicate bile duct development in addition to the albumin-secreting hepatocyte-like cells. Human albumin was not expressed in the starting stem cell populations in injured mice that did not receive transplants nor in noninjured mice that had received transplants of human stem cells. Human albumin expression was detected only in CCl(4)-treated mice that received transplants of human stem cells, and recovery was increased by administration of human hepatocyte growth factor 48 hours after the CCl(4)-mediated liver injury. Our studies provide evidence that human "hematopoietic" stem/progenitor cell populations have the capacity to respond to the injured liver microenvironment by inducing albumin expression.

Little evidence of bone marrow-derived hepatocytes in the replacement of injured liver

“…Recently, it has been suggested to be effective in inducing hepatocytic differentiation of BMC (11). Four female B6 mice were lethally irradiated and transplanted with male TgN(ActbEGFP) or TgN(MTnLacZ) BM mononuclear cells (1 ϫ 10 6 ).…”

“…We used three models: T here have been a number of reports that show the potential of adult rodent bone marrow (BM) cells (BMCs) to transdifferentiate into a variety of cell types (1-7), including hepatocytes (8 -10). One of the best examples for the transdifferentiation has been the ability of BM-derived hapatocytes to repopulate the liver of mice with fumarylacetoacetate hydrolase knockout mouse (FAHϪ͞Ϫ) and correct the liver disease (10), although recent reports have shown that this correction of liver disease is caused by fusion of donor BM to recipient hepatocytes rather than transdifferentiation (11,12). However, it is not fully elucidated whether or not the significant level of the contribution of BM-derived hepatocytes in the FAHϪ͞Ϫ model, either in the form of transdifferentiation or cell fusion, can be generalized in other liver injury models.…”

Multiorgan engraftment and differentiation of human cord blood CD34 + Lin − cells in goats assessed by gene expression profiling

“…Whether the CD34 ϩ Lin Ϫ cells derived from CB have the potential to transdifferentiate into other types of nonhematopoietic tissues in the fetal stage remains largely unexplored. Wang et al (27) reported that human albumin-expressing hepatocyte-like cells can be developed in the livers of immune-deficient and CCl 4 -injured mice that received transplants of human HSC, suggesting that human ''hematopoietic'' stem͞progenitor cells have the capacity to respond to the injured liver microenvironment by inducing albumin. A more recent study reported that human HSCs can efficiently (20%) generate functional hepatic cells in the human͞sheep model (28).…”

Activation of interleukin-6-induced glycoprotein 130/signal transducer and activator of transcription 3 pathway in mesenchymal stem cells enhances hepatic differentiation, proliferation, and liver regeneration

“…Although the therapeutic effect of stem cell transplantation is promising, previous studies have suggested that less than 1% of transplanted MSCs are constituted to the total organ mass. 25,26 The fate of stem cells after transplantation remains an important issue. In our study, we also encountered the same problem.…”