Gfi-1 restricts proliferation and preserves functional integrity of haematopoietic stem cells

Haematopoietic stem cells (HSCs) sustain blood production throughout life. HSCs are capable of extensive proliferative expansion, as a single HSC may reconstitute lethally irradiated hosts. In steady-state, HSCs remain largely quiescent and self-renew at a constant low rate, forestalling their exhau...

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Bibliographic Details
Published in:Nature 2004-10, Vol.431 (7011), p.1002-1007
Main Authors: Orkin, Stuart H, Hock, Hanno, Hamblen, Melanie J, Rooke, Heather M, Schindler, Jeffrey W, Saleque, Shireen, Fujiwara, Yuko
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Blood
Bone marrow
Bone Marrow Transplantation
Bromodeoxyuridine
Cell Cycle
Cell cycle, cell proliferation
Cell Division
Cell physiology
DNA-Binding Proteins - deficiency
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Fundamental and applied biological sciences. Psychology
Gene Deletion
Hematopoiesis
Hematopoietic Stem Cells - cytology
Hematopoietic Stem Cells - metabolism
Humanities and Social Sciences
Immunophenotyping
letter
Leukocyte Common Antigens - metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Molecular and cellular biology
multidisciplinary
Repopulation
Science
Science (multidisciplinary)
Stem cells
Transcription Factors - deficiency
Transcription Factors - genetics
Transcription Factors - metabolism
Zinc
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Summary:Haematopoietic stem cells (HSCs) sustain blood production throughout life. HSCs are capable of extensive proliferative expansion, as a single HSC may reconstitute lethally irradiated hosts. In steady-state, HSCs remain largely quiescent and self-renew at a constant low rate, forestalling their exhaustion during adult life. Whereas nuclear regulatory factors promoting proliferative programmes of HSCs in vivo and ex vivo have been identified, transcription factors restricting their cycling have remained elusive. Here we report that the zinc-finger repressor Gfi-1 (growth factor independent 1), a cooperating oncogene in lymphoid cells, unexpectedly restricts proliferation of HSCs. After loss of Gfi-1, HSCs display elevated proliferation rates as assessed by 5-bromodeoxyuridine incorporation and cell-cycle analysis. Gfi-1-/- HSCs are functionally compromised in competitive repopulation and serial transplantation assays, and are rapidly out-competed in the bone marrow of mouse chimaeras generated with Gfi-1-/- embryonic stem cells. Thus, Gfi-1 is essential to restrict HSC proliferation and to preserve HSC functional integrity.
ISSN:0028-0836
1476-4687
DOI:10.1038/nature02994