Blood, 15 May 2003, Vol. 101, No. 10, pp. 3762-3764
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 C1qRp, 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
CD38C1qR
cells. In contrast, Wang
et al detected no human hepatocytes after transplantation
of either 2000 CD34+CD38CD7 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.
Diane S. Krause
Yale University School of Medicine
