Hematopoietic stem cells depend upon G(s)α-mediated signalling to engraft bone marrow

Hematopoietic stem/progenitor cells (HSPC) transition in location during development1 and circulate in mammals throughout life2, moving into and out of the bloodstream to engage bone marrow (BM) niches in sequential steps of homing, engraftment and retention3–5. We show here that HSPC engraftment of BM in fetal development is dependent upon the guanine nucleotide binding protein stimulatory alpha subunit (G(s)α). Adult G(s)α(−/−) HSPCs differentiate and undergo chemotaxis, but also do not home to or engraft in the BM in adult mice and demonstrate marked inability to engage the marrow microvasculature. If deleted after engraftment, G(s)α did not lead to lack of retention in the marrow, rather cytokine-induced mobilization into the blood was impaired. Testing whether activation of G(s)α affects HSPC, pharmacologic activators enhanced homing and engraftment in vivo. G(s)α governs specific aspects of HSPC localization under physiologic conditions in vivo and may be pharmacologically targeted to improve transplantation efficiency.