Hinge, AshwiniXu, JuyingJavier, JoseMose, EucabethKumar, SachinKapur, ReubenSrour, Edward F.Malik, PunamAronow, Bruce J.Filippi, Marie-Dominique2017-06-272017-06-272017-02-08Hinge, A., Xu, J., Javier, J., Mose, E., Kumar, S., Kapur, R., … Filippi, M.-D. (2017). p190-B RhoGAP and intracellular cytokine signals balance hematopoietic stem and progenitor cell self-renewal and differentiation. Nature Communications, 8, 14382. http://doi.org/10.1038/ncomms14382https://hdl.handle.net/1805/13167The 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.en-USAttribution-NonCommercial-NoDerivs 3.0 United StatesHematopoietic stem cellsProgenitor cellsHSPCHSPC self-renewalHSPC differentiationProteinsIntracellular cytokine signallingArticle