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Mickie Bhatia^*, Dominique Bonnet, Dongmei Wu^*, Barbara Murdoch, Jeff Wrana, Lisa Gallacher^*, and John E. Dick

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 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

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^–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 β, 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.

Key Words: hematopoiesis • stem cells • bone morphogenetic proteins • ex vivo • xenotransplantation

D. Bonnet's present address is Coriell Institute for Medical Research, Camden, NJ 08103.

M. Bhatia and D. Bonnet contributed equally to this work.

Abbreviations used: ALK, activin-like kinase; BM, bone marrow; BMP, bone morphogenetic protein; CB, cord blood; CFC, colony-forming cell; GF, growth factor; Lin, lineage; LTC-IC, long-term culture initiating cell; M-PB, mobilized peripheral blood; NOD, nonobese diabetic; RT, reverse transcription; SRC, SCID-repopulating cell.

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