Xenogeneic studies of human stem cell plasticity

Differentiation of bone marrow–derived stem cells (BMSC) into mature hepatocytes occurs in mice and humans (reviewed in Theise and Krause, Leukemia. 2002;16:542-548). Murine studies show that the same BM subpopulations that are capable of engraftment of the hematopoietic system are capable of differentiation into mature hepatocytes in vivo. Because analogous studies using limiting numbers of specific cell subpopulations cannot be performed in humans, xenogeneic and in vitro systems are needed in order to determine which human cell subpopulations can differentiate into hepatocytes. More importantly, these models can then be used to determine the mechanism by which this occurs.

In this issue of Blood, the article by Wang and colleagues (page 4201) represents a significant contribution to the developing story regarding the plasticity of BMSC because it shows not only that human CD34⁺ cord blood (CB) and BM cells are capable of differentiating into hepatocytes, but also that specific forms of hepatic damage enhance the levels of engraftment.

The data presented corroborate those of Danet et al (Proc Natl Acad Sci U S A. 2002;99:10441-10445), which showed that human CB and BM cells expressing the complement receptor C1qR_p, the human homologue of murine AA4.1, differentiate into mature hepatocytes in the livers of immunodeficient mice. Although NOD/SCID mice were sublethally irradiated prior to transplantation of human cells in both studies, the in vivo conditions required to detect human hepatocytes in the mice differed. Danet et al detected fewer than 0.1% human hepatocytes after mice were irradiated with 375 cGy and received as few as 5000 lin⁻CD38⁻C1qR$p+$ cells. In contrast, Wang et al detected no human hepatocytes after transplantation of either 2000 CD34⁺CD38⁻CD7⁻ or 1 × 10⁵ CD34⁺ cells into mice irradiated with 300 cGy, which could be due to differences in the cell populations, the amount of irradiation, or the detection methods used. In Wang et al, specific liver damage was critical for induction of hepatocyte engraftment. Engraftment occurred after administration of the hepatotoxic agent CCl₄ and was further enhanced by administration of hepatocyte growth factor. Neither irradiation alone nor irradiation plus allyl alcohol treatment induced human hepatocyte formation.

Development of this xenogeneic model of human hepatocyte differentiation from human CB and BM paves the way for further advances in our understanding of plasticity. In addition to developing methods for obtaining physiologically relevant levels of human hepatocyte engraftment, this xenogeneic model will be useful for studies of human hepatocyte function and dysfunction in inherited diseases as well as viral hepatitis.