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GATA-3 regulates the self-renewal of long-term hematopoietic stem cells

Nature Immunology volume 14, pages 1037–1044 (2013)Cite this article

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Abstract

The transcription factor GATA-3 is expressed and required for differentiation and function throughout the T lymphocyte lineage. Despite evidence it may also be expressed in multipotent hematopoietic stem cells (HSCs), any role for GATA-3 in these cells has remained unclear. Here we found GATA-3 was in the cytoplasm in quiescent long-term stem cells from steady-state bone marrow but relocated to the nucleus when HSCs cycled. Relocation depended on signaling via the mitogen-activated protein kinase p38 and was associated with a diminished capacity for long-term reconstitution after transfer into irradiated mice. Deletion of Gata3 enhanced the repopulating capacity and augmented the self-renewal of long-term HSCs in cell-autonomous fashion without affecting the cell cycle. Our observations position GATA-3 as a regulator of the balance between self-renewal and differentiation in HSCs that acts downstream of the p38 signaling pathway.

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Figure 1: Gata3 is actively transcribed in LT-HSCs but not in IT-HSCs.
Figure 2: GATA-3 is expressed in LT-HSCs but not in IT-HSCs.
Figure 3: GATA-3 relocalizes to the nucleus in cycling cells and the effect is inhibited by inhibitors of p38α.
Figure 4: Treatment with poly(I:C) induces HSC cycling and relocalization of GATA-3 in vivo and reduces the long-term reconstituting capacity of wild-type LSKRα2lo cells.
Figure 5: Gata3 excision has little effect on steady-state bone marrow and blood populations.
Figure 6: Regenerative activity and self-renewal are enhanced in vivo and in vitro after deletion of Gata3.

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Acknowledgements

We thank F. Melchers (Max Planck Institute for Infection Biology) for conditioned medium from transduced mouse cells that produce IL-7; P.A. Penttilä for assistance with flow cytometry and M.F. Monroy for help with animal procedures. Supported by the Terry Fox Foundation, the Canadian Cancer Research Institute, the Canadian Institutes of Health Research, the Stem Cell Network, the Fondation de France (C.F.), the Fondation pour la Recherche Médicale (C.F.), the McEwen Centre for Regenerative Medicine, the Princess Margaret Hospital Foundation, the Campbell Family Institute for Cancer Research and the Ontario Ministry of Health and Long Term Care. The views expressed do not necessarily reflect those of the Ontario Ministry of Health and Long Term Care.

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Authors and Affiliations

  1. Ontario Cancer Institute, University Health Network, Toronto, Canada

    Catherine Frelin, Robert Herrington, Mary Barbara, Gary Tran, Christopher J Paige & Norman N Iscove

  2. Department of Medical Biophysics, University of Toronto, Toronto, Canada

    Catherine Frelin, Gary Tran, Christopher J Paige & Norman N Iscove

  3. Department of Immunology, University of Toronto, Toronto, Canada

    Salima Janmohamed, Christopher J Paige, Patricia Benveniste, Juan-Carlos Zuñiga-Pflücker & Norman N Iscove

  4. Sunnybrook Research Institute, Toronto, Canada

    Patricia Benveniste & Juan-Carlos Zuñiga-Pflücker

  5. Research Institute of Molecular Pathology, Vienna, Austria

    Abdallah Souabni & Meinrad Busslinger

  6. McEwen Centre for Regenerative Medicine, Toronto, Canada

    Norman N Iscove

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Contributions

C.F. did most of the experimental work; C.F. and N.N.I. wrote the manuscript; S.J., G.T., C.J.P., P.B. and J.-C.Z.-P. contributed some data elements; R.H. and M.B. provided technical support; and A.S. and M.B. engineered and supplied the Gata3 mutant mice and helped write the manuscript.

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Correspondence to Norman N Iscove.

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Frelin, C., Herrington, R., Janmohamed, S. et al. GATA-3 regulates the self-renewal of long-term hematopoietic stem cells. Nat Immunol 14, 1037–1044 (2013). https://doi.org/10.1038/ni.2692

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