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.
Skip Nav Destination
Article navigation
5 April 1999
Article|
April 05 1999
Bone Morphogenetic Proteins Regulate the Developmental Program of Human Hematopoietic Stem Cells
Mickie Bhatia,
Mickie Bhatia
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
Search for other works by this author on:
Dominique Bonnet,
Dominique Bonnet
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
Search for other works by this author on:
Dongmei Wu,
Dongmei Wu
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
Search for other works by this author on:
Barbara Murdoch,
Barbara Murdoch
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
Search for other works by this author on:
Jeff Wrana,
Jeff Wrana
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
Search for other works by this author on:
Lisa Gallacher,
Lisa Gallacher
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
Search for other works by this author on:
John E. Dick
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
Search for other works by this author on:
Mickie Bhatia
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
Dominique Bonnet
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
Dongmei Wu
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
Barbara Murdoch
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
Jeff Wrana
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
Lisa Gallacher
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
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
Address correspondence to Mickie Bhatia, The John P. Robarts Research Institute, Gene Therapy and Molecular Virology, 100 Perth Dr., London, Ontario N6A 5K8, Canada. Phone: 519-663-5777 ext. 4166; Fax: 519-663-3789; E-mail: [email protected]
D. Bonnet's present address is Coriell Institute for Medical Research, Camden, NJ 08103.
M. Bhatia and D. Bonnet contributed equally to this work.
Received:
November 20 1998
Revision Received:
January 20 1999
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1999
J Exp Med (1999) 189 (7): 1139–1148.
Article history
Received:
November 20 1998
Revision Received:
January 20 1999
Citation
Mickie Bhatia, Dominique Bonnet, Dongmei Wu, Barbara Murdoch, Jeff Wrana, Lisa Gallacher, John E. Dick; Bone Morphogenetic Proteins Regulate the Developmental Program of Human Hematopoietic Stem Cells . J Exp Med 5 April 1999; 189 (7): 1139–1148. doi: https://doi.org/10.1084/jem.189.7.1139
Download citation file:
Sign in
Don't already have an account? Register
Client Account
You could not be signed in. Please check your email address / username and password and try again.
Could not validate captcha. Please try again.
Sign in via your Institution
Sign in via your InstitutionSuggested Content
Email alerts
Advertisement
