Letters to Nature

Nature 423, 302-305 (15 May 2003) | doi:10.1038/nature01587; Received 10 February 2003; Accepted 19 March 2003; Published online 20 April 2003

Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells

In-kyung Park1, Dalong Qian1, Mark Kiel2, Michael W. Becker1, Michael Pihalja1, Irving L. Weissman3, Sean J. Morrison2 & Michael F. Clarke1

  1. Division of Hematology/Oncology, Internal Medicine, and Howard Hughes Medical Institute, Department of Internal Medicine, and Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA
  2. Department of Pathology, School of Medicine, Stanford University, Stanford, California 94305, USA

Correspondence to: Michael F. Clarke1 Correspondence and requests for materials should be addressed to M.F.C. (Email: mclarke@umich.edu).

A central issue in stem cell biology is to understand the mechanisms that regulate the self-renewal of haematopoietic stem cells (HSCs), which are required for haematopoiesis to persist for the lifetime of the animal1. We found that adult and fetal mouse and adult human HSCs express the proto-oncogene Bmi-1. The number of HSCs in the fetal liver of Bmi-1 -/- mice2 was normal. In postnatal Bmi-1 -/- mice, the number of HSCs was markedly reduced. Transplanted fetal liver and bone marrow cells obtained from Bmi-1 -/- mice were able to contribute only transiently to haematopoiesis. There was no detectable self-renewal of adult HSCs, indicating a cell autonomous defect in Bmi-1 -/- mice. A gene expression analysis revealed that the expression of stem cell associated genes3, cell survival genes, transcription factors, and genes modulating proliferation including p16 Ink4a and p19 Arf was altered in bone marrow cells of the Bmi-1 -/- mice. Expression of p16 Ink4a and p19 Arf in normal HSCs resulted in proliferative arrest and p53-dependent cell death, respectively. Our results indicate that Bmi-1 is essential for the generation of self-renewing adult HSCs.