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Prdm16 promotes stem cell maintenance in multiple tissues, partly by regulating oxidative stress

Nature Cell Biology volume 12, pages 999–1006 (2010)Cite this article

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Abstract

To better understand the mechanisms that regulate stem cell identity and function, we sought to identify genes that are preferentially expressed by stem cells and critical for their function in multiple tissues. Prdm16 is a transcription factor that regulates leukaemogenesis1, palatogenesis2 and brown-fat development3,4,5, but which was not known to be required for stem cell function. We demonstrate that Prdm16 is preferentially expressed by stem cells throughout the nervous and haematopoietic systems and is required for their maintenance. In the haematopoietic and nervous systems, Prdm16 deficiency led to changes in the levels of reactive oxygen species (ROS), depletion of stem cells, increased cell death and altered cell-cycle distribution. In neural stem/progenitor cells, Prdm16 binds to the Hgf promoter, and Hgf expression declined in the absence of Prdm16. Addition of recombinant HGF to Prdm16-deficient neural stem cells in cell culture reduced the depletion of these cells and partially rescued the increase in ROS levels. Administration of the anti-oxidant, N-acetyl-cysteine, to Prdm16-deficient mice partially rescued defects in neural stem/progenitor cell function and neural development. Prdm16 therefore promotes stem cell maintenance in multiple tissues, partly by modulating oxidative stress.

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Figure 1: Prdm16 is preferentially expressed by stem cells and primitive progenitors in the haematopoietic and nervous systems.
Figure 2: Prdm16 is required for survival, cell-cycle regulation and maintenance, in fetal and adult HSCs.
Figure 3: Prdm16 is required for survival, cell-cycle regulation and self-renewal in neural stem cells.
Figure 4: Prdm16 promotes the expression of Hgf and regulates ROS levels in neural stem/progenitor cells.
Figure 5: Prdm16 promotes neural stem/progenitor cell function by regulating Hgf expression and ROS levels.

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Acknowledgements

This work was supported by the Howard Hughes Medical Institute and by the National Institutes of Neurological Disease and Stroke (NS40750). S.C. was supported by a career development award from the Leukemia and Lymphoma Society. B.P.L. was supported by an American Heart Association Postdoctoral Fellowship (0725726Z) and an Irvington Institute-Cancer Research Institute/Edmond J. Safra Memorial Fellowship. Flow-cytometry work was partially supported by the UM-Comprehensive Cancer, NIH CA46592. We thank M. White and D. Adams for flow-cytometry assistance, G. Wendt for technical assistance, and E. Smith (Hybridoma Core Facility) for antibody production, partially supported through the Rheumatic Core Disease Center (P30 AR48310).

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  1. Sergei Chuikov and Boaz P. Levi: These authors contributed equally to this work

Authors and Affiliations

  1. Howard Hughes Medical Institute University of Michigan, 210 Washtenaw Avenue, Ann Arbor, 48109-2216, MI, USA

    Sergei Chuikov, Boaz P. Levi, Michael L. Smith & Sean J. Morrison

  2. Department of Internal Medicine, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, 48109-2216, MI, USA

    Sergei Chuikov, Boaz P. Levi, Michael L. Smith & Sean J. Morrison

  3. Center for Stem Cell Biology, Life Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, 48109-2216, MI, USA

    Sergei Chuikov, Boaz P. Levi, Michael L. Smith & Sean J. Morrison

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Contributions

S.C. and B.P.L. characterized Prdm16 expression and function with assistance from M.L.S. S.C., B.P.L., and S.J.M. designed experiments, interpreted results and wrote the manuscript.

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Correspondence to Sean J. Morrison.

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The authors declare no competing financial interests.

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Chuikov, S., Levi, B., Smith, M. et al. Prdm16 promotes stem cell maintenance in multiple tissues, partly by regulating oxidative stress. Nat Cell Biol 12, 999–1006 (2010). https://doi.org/10.1038/ncb2101

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