|
||
J. Exp. Med.,
Volume 189, Number 7, April 5, 1999 1139-1148
By




From the * Department of Gene Therapy and Molecular Virology, The John P. Robarts Research
Institute, and the Department of Microbiology and Immunology, University of Western Ontario,
London, Ontario N6A 5K8, Canada; and the The identification of molecules that regulate human hematopoietic stem cells has focused
mainly on cytokines, of which very few are known to act directly on stem cells. Recent studies
in lower organisms and the mouse have suggested that bone morphogenetic proteins (BMPs)
may play a critical role in the specification of hematopoietic tissue from the mesodermal germ
layer. Here we report that BMPs regulate the proliferation and differentiation of highly purified
primitive human hematopoietic cells from adult and neonatal sources. Populations of rare
CD34+CD38
Program in Cancer/Blood and the Program in
Developmental Biology, Research Institute, Hospital for Sick Children, and the Department of
Molecular and Medical Genetics, University of Toronto, Toronto, Ontario M5G 1X8, Canada
Lin
stem cells were isolated from human hematopoietic tissue and were found
to express the BMP type I receptors activin-like kinase (ALK)-3 and ALK-6, and their downstream transducers SMAD-1, -4, and -5. Treatment of isolated stem cell populations with soluble BMP-2, -4, and -7 induced dose-dependent changes in proliferation, clonogenicity, cell
surface phenotype, and multilineage repopulation capacity after transplantation in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Similar to transforming growth factor
, treatment of purified cells with BMP-2 or -7 at high concentrations inhibited proliferation yet maintained the primitive CD34+CD38
phenotype and repopulation capacity. In
contrast, low concentrations of BMP-4 induced proliferation and differentiation of CD34+
CD38
Lin
cells, whereas at higher concentrations BMP-4 extended the length of time that
repopulation capacity could be maintained in ex vivo culture, indicating a direct effect on stem
cell survival. The discovery that BMPs are capable of regulating repopulating cells provides a
new pathway for controlling human stem cell development and a powerful model system for
studying the biological mechanism of BMP action using primary human cells.
This article has been cited by other articles:
| TABLE OF CONTENTS |
|