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

Abstract

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 p16Ink4a and p19Arf was altered in bone marrow cells of the Bmi-1-/- mice. Expression of p16Ink4a and p19Arf 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.

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Figure 1: Analysis of adult HSCs.
Figure 2: Analysis of fetal liver haematopoietic stem cells in Bmi-1+/+, Bmi-1+/- and Bmi-1-/- mice.
Figure 3: Regulation of gene expression by Bmi-1.
Figure 4: Effects of p16Ink4a and p19Arf on HSC proliferation.
Figure 5: Proposed model for the role of Bmi-1 in HSC maintenance.

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Acknowledgements

We thank T. Magnuson and C. Klug for providing Bmi-1+/- mice and the MSCV plasmid, respectively; and the Flow Cytometry Core and the Microarray Core at the University of Michigan for their work. The Microarray Core is supported in part by a University of Michigan's Cancer Center Support Grant from the NIH. This work is supported by grants from the NIH.

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Correspondence to Michael F. Clarke.

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The authors declare that they have no competing financial interests.

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Park, I., Qian, D., Kiel, M. et al. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423, 302–305 (2003). https://doi.org/10.1038/nature01587

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