RARgamma is critical for maintaining a balance between hematopoietic stem cell self-renewal and differentiation. - Archive ouverte HAL Access content directly
Journal Articles Journal of Experimental Medicine Year : 2006

RARgamma is critical for maintaining a balance between hematopoietic stem cell self-renewal and differentiation.

Louise E Purton
  • Function : Author
Sebastian Dworkin
  • Function : Author
Gemma Haines Olsen
  • Function : Author
Carl R Walkley
  • Function : Author
Stewart A Fabb
  • Function : Author
Steven J Collins
  • Function : Author

Abstract

Hematopoietic stem cells (HSCs) sustain lifelong production of all blood cell types through finely balanced divisions leading to self-renewal and differentiation. Although several genes influencing HSC self-renewal have been identified, to date no gene has been described that, when activated, enhances HSC self-renewal and, when inactivated [corrected] promotes HSC differentiation. We observe that the retinoic acid receptor (RAR)gamma is selectively expressed in primitive hematopoietic precursors and that the bone marrow of RARgamma knockout mice exhibit markedly reduced numbers of HSCs associated with increased numbers of more mature progenitor cells compared with wild-type mice. In contrast, RARalpha is widely expressed in hematopoietic cells, but RARalpha knockout mice do not exhibit any HSC or progenitor abnormalities. Primitive hematopoietic precursors overexpressing RARalpha differentiate predominantly to granulocytes in short-term culture, whereas those overexpressing RARgamma exhibit a much more undifferentiated phenotype. Furthermore, loss of RARgamma abrogated the potentiating effects of all-trans retinoic acid on the maintenance of HSCs in ex vivo culture. Finally, pharmacological activation of RARgamma ex vivo promotes HSC self-renewal, as demonstrated by serial transplant studies. We conclude that the RARs have distinct roles in hematopoiesis and that RARgamma is a critical physiological and pharmacological regulator of the balance between HSC self-renewal and differentiation.

Dates and versions

hal-00188114 , version 1 (15-11-2007)

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Louise E Purton, Sebastian Dworkin, Gemma Haines Olsen, Carl R Walkley, Stewart A Fabb, et al.. RARgamma is critical for maintaining a balance between hematopoietic stem cell self-renewal and differentiation.. Journal of Experimental Medicine, 2006, 203 (5), pp.1283-93. ⟨10.1084/jem.20052105⟩. ⟨hal-00188114⟩
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