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 (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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Mikkola, H. K. A. & Orkin, S. H. The journey of developing hematopoietic stem cells. Development 133, 3733–3744 (2006)
Wright, D. E., Wagers, A. J., Gulati, A. P., Johnson, F. L. & Weissman, I. L. Physiological migration of hematopoietic stem and progenitor cells. Science 294, 1933–1936 (2001)
Mazo, I. B. et al. Hematopoietic progenitor cell rolling in bone marrow microvessels: parallel contributions by endothelial selectins and vascular cell adhesion molecule 1. J. Exp. Med. 188, 465–474 (1998)
Papayannopoulou, T., Priestley, G. V., Nakamoto, B., Zafiropoulos, V. & Scott, L. M. Molecular pathways in bone marrow homing: dominant role of α4β1 over β2-integrins and selectins. Blood 98, 2403–2411 (2001)
Lapidot, T., Dar, A. & Kollet, O. How do stem cells find their way home? Blood 106, 1901–1910 (2005)
Yu, S. et al. Variable and tissue-specific hormone resistance in heterotrimeric Gs protein α-subunit (Gsα) knockout mice is due to tissue-specific imprinting of the Gsα gene. Proc. Natl Acad. Sci. USA 95, 8715–8720 (1998)
Bastepe, M. et al. Stimulatory G protein directly regulates hypertrophic differentiation of growth plate cartilage in vivo . Proc. Natl Acad. Sci. USA 101, 14794–14799 (2004)
Dexter, T. M., Whetton, A. D. & Heyworth, C. M. Inhibitors of cholera toxin-induced adenosine diphosphate ribosylation of membrane-associated proteins block stem cell differentiation. Blood 65, 1544–1548 (1985)
Long, M. W., Heffner, C. H. & Gragowski, L. L. Cholera toxin and phorbol diesters synergistically modulate murine hematopoietic progenitor cell proliferation. Exp. Hematol. 16, 195–200 (1988)
Ploemacher, R. E., van der Sluijs, J. P., van Beurden, C. A., Baert, M. R. & Chan, P. L. Use of limiting-dilution type long-term marrow cultures in frequency analysis of marrow-repopulating and spleen colony-forming hematopoietic stem cells in the mouse. Blood 78, 2527–2533 (1991)
Wright, D. E., Bowman, E. P., Wagers, A. J., Butcher, E. C. & Weissman, I. L. Hematopoietic stem cells are uniquely selective in their migratory response to chemokines. J. Exp. Med. 195, 1145–1154 (2002)
Sipkins, D. A. et al. In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment. Nature 435, 969–973 (2005)
North, T. E. et al. Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature 447, 1007–1011 (2007)
Nagasawa, T. et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 382, 635–638 (1996)
Ma, Q. et al. Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. Proc. Natl Acad. Sci. USA 95, 9448–9453 (1998)
Broxmeyer, H. E. et al. AMD3100 and CD26 modulate mobilization, engraftment, and survival of hematopoietic stem and progenitor cells mediated by the SDF-1/CXCL12-CXCR4 axis. Ann. NY Acad. Sci. 1106, 1–19 (2007)
Foudi, A. et al. Reduced retention of radioprotective hematopoietic cells within the bone marrow microenvironment in CXCR4-/- chimeric mice. Blood 107, 2243–2251 (2006)
Kawabata, K. et al. A cell-autonomous requirement for CXCR4 in long-term lymphoid and myeloid reconstitution. Proc. Natl Acad. Sci. USA 96, 5663–5667 (1999)
Calvi, L. M. et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425, 841–846 (2003)
Cheng, T. et al. Hematopoietic stem cell quiescence maintained by p21cip1/waf1 . Science 287, 1804–1808 (2000)
Stier, S., Cheng, T., Dombkowski, D., Carlesso, N. & Scadden, D. T. Notch1 activation increases hematopoietic stem cell self-renewal in vivo and favors lymphoid over myeloid lineage outcome. Blood 99, 2369–2378 (2002)
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.).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
D.T.S. is a consultant for and stockholder of Fate Therapeutics, Inc.
Supplementary information
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)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nature07859
This article is cited by
-
Functions and regulatory mechanisms of resting hematopoietic stem cells: a promising targeted therapeutic strategy
Stem Cell Research & Therapy (2023)
-
New aspects of HSC mobilization for better therapeutic outcomes
Cellular & Molecular Immunology (2021)
-
Nociceptive nerves regulate haematopoietic stem cell mobilization
Nature (2021)
-
Hematopoietic Stem Cell Mobilization: Current Collection Approaches, Stem Cell Heterogeneity, and a Proposed New Method for Stem Cell Transplant Conditioning
Stem Cell Reviews and Reports (2021)
-
Regimen-dependent synergism and antagonism of treprostinil and vildagliptin in hematopoietic cell transplantation
Journal of Molecular Medicine (2020)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.