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Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches

Nature volume 495, pages 231–235 (2013)Cite this article

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An Erratum to this article was published on 08 October 2014

Abstract

Although haematopoietic stem cells (HSCs) are commonly assumed to reside within a specialized microenvironment, or niche1, most published experimental manipulations of the HSC niche have affected the function of diverse restricted progenitors. This raises the fundamental question of whether HSCs1 and restricted progenitors2,3 reside within distinct, specialized niches or whether they share a common niche. Here we assess the physiological sources of the chemokine CXCL12 for HSC and restricted progenitor maintenance. Cxcl12DsRed knock-in mice (DsRed-Express2 recombined into the Cxcl12 locus) showed that Cxcl12 was primarily expressed by perivascular stromal cells and, at lower levels, by endothelial cells, osteoblasts and some haematopoietic cells. Conditional deletion of Cxcl12 from haematopoietic cells or nestin–cre-expressing cells had little or no effect on HSCs or restricted progenitors. Deletion of Cxcl12 from endothelial cells depleted HSCs but not myeloerythroid or lymphoid progenitors. Deletion of Cxcl12 from perivascular stromal cells depleted HSCs and certain restricted progenitors and mobilized these cells into circulation. Deletion of Cxcl12 from osteoblasts depleted certain early lymphoid progenitors but not HSCs or myeloerythroid progenitors, and did not mobilize these cells into circulation. Different stem and progenitor cells thus reside in distinct cellular niches in bone marrow: HSCs occupy a perivascular niche and early lymphoid progenitors occupy an endosteal niche.

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Figure 1: Endothelial cells and perivascular stromal cells are the major sources of Cxcl12 in bone marrow.
Figure 2: CXCL12 produced by endothelial cells promotes HSC maintenance.
Figure 3: CXCL12 produced by Lepr -expressing perivascular stromal cells retains HSCs and colony-forming progenitors in the bone marrow.
Figure 4: CXCL12 produced by osteoblasts promotes the maintenance of early lymphoid progenitors but not HSCs.

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Acknowledgements

This work was supported by the Howard Hughes Medical Institute (HHMI) and the US National Heart, Lung and Blood Institute (5R01-HL097760). L.D. was supported by a Helen Hay Whitney Foundation Fellowship and by the HHMI. We thank M. White and D. Adams for flow cytometry, E. Hughes and T. Saunders at the University of Michigan transgenic core for helping to generate Cxcl12DsRed and Cxcl12fl mice, and S. Grove, R. Coolon, S. Manning, M. Gross and K. Correll for managing the mouse colony.

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  1. Department of Pediatrics, Howard Hughes Medical Institute, Children’s Research Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA,

    Lei Ding & Sean J. Morrison

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  1. Lei Ding
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L.D. performed all of the experiments. L.D. and S.J.M. conceived the project, designed the experiments, interpreted the results and wrote the manuscript.

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Correspondence to Sean J. Morrison.

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The authors declare no competing financial interests.

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Ding, L., Morrison, S. Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches. Nature 495, 231–235 (2013). https://doi.org/10.1038/nature11885

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