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

Abstract

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 (s-/-) 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.

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Figure 1: s is required for HSPC engraftment of bone marrow in development.
Figure 2: s is required for HSPC engraftment of bone marrow in adults.
Figure 3: s signalling is not required for retention of the HSPCs in the bone marrow, but does influence mobilization by G-CSF.
Figure 4: Pharmacological modulation of Gα s affects homing and engraftment of primitive wild-type bone-marrow MNCs.

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Acknowledgements

Financial support for this work was provided by the Burroughs Wellcome Fund, Doris Duke Charitable Trust (D.T.S.), the Harvard Stem Cell Institute (C.P.L.) and the National Institutes of Health (G.B.A., C.P.L., H.M.K., D.T.S.).

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Correspondence to David T. Scadden.

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D.T.S. is a consultant for and stockholder of Fate Therapeutics, Inc.

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Supplementary Information

This file contains Supplementary Figures 1-11 with Legends and Supplementary Movie Legends 1-2. (PDF 606 kb)

Supplementary Movie 1

This movie shows Trafficking of Mx1-Cre WT LKS+ cells in bone marrow microvasculature (see file s1 for full movie legend). (MOV 2992 kb)

Supplementary Movie 2

This movie shows Trafficking of Mx1-Cre KO LKS+ cells in bone marrow microvasculature (see file s1 for full movie legend). (MOV 5570 kb)

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Adams, G., Alley, I., Chung, Ui. et al. Haematopoietic stem cells depend on Gαs-mediated signalling to engraft bone marrow. Nature 459, 103–107 (2009). https://doi.org/10.1038/nature07859

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