Haematopoietic stem cells depend on Gαs-mediated signalling to engraft bone marrow

Abstract

Gαs signalling, a pathway previously not recognized as having a role in stem-cell biology, has been found to be critical in haematopoiesis in the developing fetus (without it cells do not transition from the fetal liver to the bone marrow) and in adult mice (without it cells do not engraft the bone marrow). Haematopoietic stem and progenitor cells that lack Gαs (the guanine-nucleotide-binding protein stimulatory α subunit) differentiate and undergo chemotaxis, but are unable to home in on their usual sites of action. Cholera toxin, a compound known to constitutively activate Gαs, enhanced stem-cell homing and engraftment in mice, suggesting that similar strategies could be used to improve the efficiency in transplants of human blood-forming stem cells. Currently massive numbers of blood-forming stem cells are used in clinical transplantation, in part due to inefficient homing and engraftment. The guanine-nucleotide-binding protein stimulatory α subunit (Gαs) is necessary for the homing and engraftment of haematopoietic stem and progenitor cells to bone marrow, as demonstrated by its disruption in adult mice deficient in Gαs. Conversely, pharmacological activators of Gαs enhance homing and engraftment in vivo, suggesting a potential pharmacological target to improve transplantation efficiency. Haematopoietic stem and progenitor cells (HSPCs) change location during development1 and circulate in mammals throughout life2, moving into and out of the bloodstream to engage bone marrow niches in sequential steps of homing, engraftment and retention3,4,5. Here we show that HSPC engraftment of bone marrow in fetal development is dependent on the guanine-nucleotide-binding protein stimulatory α subunit (Gαs). HSPCs from adult mice deficient in Gαs (Gαs-/-) differentiate and undergo chemotaxis, but also do not home to or engraft in the bone marrow in adult mice and demonstrate a marked inability to engage the marrow microvasculature. If deleted after engraftment, Gαs deficiency did not lead to lack of retention in the marrow, rather cytokine-induced mobilization into the blood was impaired. Testing whether activation of Gαs affects HSPCs, pharmacological activators enhanced homing and engraftment in vivo. Gαs governs specific aspects of HSPC localization under physiological conditions in vivo and may be pharmacologically targeted to improve transplantation efficiency.