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p190-B RhoGAP and intracellular cytokine signals balance hematopoietic stem and progenitor cell self-renewal and differentiation

Author

Listed:
  • Ashwini Hinge

    (Cincinnati Children's Research Foundation, University of Cincinnati College of Medicine)

  • Juying Xu

    (Cincinnati Children's Research Foundation, University of Cincinnati College of Medicine)

  • Jose Javier

    (Cincinnati Children's Research Foundation, University of Cincinnati College of Medicine)

  • Eucabeth Mose

    (Cincinnati Children's Research Foundation, University of Cincinnati College of Medicine)

  • Sachin Kumar

    (Cincinnati Children's Research Foundation, University of Cincinnati College of Medicine)

  • Reuben Kapur

    (Indiana University School of Medicine)

  • Edward F. Srour

    (Indiana University School of Medicine)

  • Punam Malik

    (Cincinnati Children's Research Foundation, University of Cincinnati College of Medicine)

  • Bruce J. Aronow

    (Cincinnati Children’s Research Foundation, University of Cincinnati College of Medicine)

  • Marie-Dominique Filippi

    (Cincinnati Children's Research Foundation, University of Cincinnati College of Medicine)

Abstract

The mechanisms regulating hematopoietic stem and progenitor cell (HSPC) fate choices remain ill-defined. Here, we show that a signalling network of p190-B RhoGAP-ROS-TGF-β-p38MAPK balances HSPC self-renewal and differentiation. Upon transplantation, HSPCs express high amounts of bioactive TGF-β1 protein, which is associated with high levels of p38MAPK activity and loss of HSC self-renewal in vivo. Elevated levels of bioactive TGF-β1 are associated with asymmetric fate choice in vitro in single HSPCs via p38MAPK activity and this is correlated with the asymmetric distribution of activated p38MAPK. In contrast, loss of p190-B, a RhoGTPase inhibitor, normalizes TGF-β levels and p38MAPK activity in HSPCs and is correlated with increased HSC self-renewal in vivo. Loss of p190-B also promotes symmetric retention of multi-lineage capacity in single HSPC myeloid cell cultures, further suggesting a link between p190-B-RhoGAP and non-canonical TGF-β signalling in HSPC differentiation. Thus, intracellular cytokine signalling may serve as ‘fate determinants’ used by HSPCs to modulate their activity.

Suggested Citation

  • Ashwini Hinge & Juying Xu & Jose Javier & Eucabeth Mose & Sachin Kumar & Reuben Kapur & Edward F. Srour & Punam Malik & Bruce J. Aronow & Marie-Dominique Filippi, 2017. "p190-B RhoGAP and intracellular cytokine signals balance hematopoietic stem and progenitor cell self-renewal and differentiation," Nature Communications, Nature, vol. 8(1), pages 1-14, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14382
    DOI: 10.1038/ncomms14382
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