Identification of a clonally expanding haematopoietic compartment in bone marrow

L. Wang; R. Benedito; M.G. Bixel; D. Zeuschner; M. Stehling; L. Savendahl; J.J. Haigh; H. Snippert; H. Clevers; G. Breier; F. Kiefer; R.H. Adams

doi:10.1038/emboj.2012.308

Identification of a clonally expanding haematopoietic compartment in bone marrow

L. Wang, R. Benedito, M.G. Bixel, D. Zeuschner, M. Stehling, L. Savendahl, J.J. Haigh, H. Snippert, H. Clevers, G. Breier, F. Kiefer, R.H. Adams

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

64 Citations (Scopus)

Abstract

In mammals, postnatal haematopoiesis occurs in the bone marrow (BM) and involves specialized microenvironments controlling haematopoietic stem cell (HSC) behaviour and, in particular, stem cell dormancy and self-renewal. While these processes have been linked to a number of different stromal cell types and signalling pathways, it is currently unclear whether BM has a homogenous architecture devoid of structural and functional partitions. Here, we show with genetic labelling techniques, high-resolution imaging and functional experiments in mice that the periphery of the adult BM cavity harbours previously unrecognized compartments with distinct properties. These units, which we have termed hemospheres, were composed of endothelial, haematopoietic and mesenchymal cells, were enriched in CD150+ CD48- putative HSCs, and enabled rapid haematopoietic cell proliferation and clonal expansion. Inducible gene targeting of the receptor tyrosine kinase VEGFR2 in endothelial cells disrupted hemospheres and, concomitantly, reduced the number of CD150+ CD48- cells. Our results identify a previously unrecognized, vessel-associated BM compartment with a specific localization and properties distinct from the marrow cavity.

Original language	English
Pages (from-to)	219-230
Journal	EMBO Journal
Volume	32
Issue number	2
DOIs	https://doi.org/10.1038/emboj.2012.308
Publication status	Published - 2013

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10.1038/emboj.2012.308

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title = "Identification of a clonally expanding haematopoietic compartment in bone marrow",

abstract = "In mammals, postnatal haematopoiesis occurs in the bone marrow (BM) and involves specialized microenvironments controlling haematopoietic stem cell (HSC) behaviour and, in particular, stem cell dormancy and self-renewal. While these processes have been linked to a number of different stromal cell types and signalling pathways, it is currently unclear whether BM has a homogenous architecture devoid of structural and functional partitions. Here, we show with genetic labelling techniques, high-resolution imaging and functional experiments in mice that the periphery of the adult BM cavity harbours previously unrecognized compartments with distinct properties. These units, which we have termed hemospheres, were composed of endothelial, haematopoietic and mesenchymal cells, were enriched in CD150+ CD48- putative HSCs, and enabled rapid haematopoietic cell proliferation and clonal expansion. Inducible gene targeting of the receptor tyrosine kinase VEGFR2 in endothelial cells disrupted hemospheres and, concomitantly, reduced the number of CD150+ CD48- cells. Our results identify a previously unrecognized, vessel-associated BM compartment with a specific localization and properties distinct from the marrow cavity.",

author = "L. Wang and R. Benedito and M.G. Bixel and D. Zeuschner and M. Stehling and L. Savendahl and J.J. Haigh and H. Snippert and H. Clevers and G. Breier and F. Kiefer and R.H. Adams",

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T1 - Identification of a clonally expanding haematopoietic compartment in bone marrow

AU - Wang, L.

AU - Benedito, R.

AU - Bixel, M.G.

AU - Zeuschner, D.

AU - Stehling, M.

AU - Savendahl, L.

AU - Haigh, J.J.

AU - Snippert, H.

AU - Clevers, H.

AU - Breier, G.

AU - Kiefer, F.

AU - Adams, R.H.

N1 - Reporting year: 2013

PY - 2013

Y1 - 2013

N2 - In mammals, postnatal haematopoiesis occurs in the bone marrow (BM) and involves specialized microenvironments controlling haematopoietic stem cell (HSC) behaviour and, in particular, stem cell dormancy and self-renewal. While these processes have been linked to a number of different stromal cell types and signalling pathways, it is currently unclear whether BM has a homogenous architecture devoid of structural and functional partitions. Here, we show with genetic labelling techniques, high-resolution imaging and functional experiments in mice that the periphery of the adult BM cavity harbours previously unrecognized compartments with distinct properties. These units, which we have termed hemospheres, were composed of endothelial, haematopoietic and mesenchymal cells, were enriched in CD150+ CD48- putative HSCs, and enabled rapid haematopoietic cell proliferation and clonal expansion. Inducible gene targeting of the receptor tyrosine kinase VEGFR2 in endothelial cells disrupted hemospheres and, concomitantly, reduced the number of CD150+ CD48- cells. Our results identify a previously unrecognized, vessel-associated BM compartment with a specific localization and properties distinct from the marrow cavity.

AB - In mammals, postnatal haematopoiesis occurs in the bone marrow (BM) and involves specialized microenvironments controlling haematopoietic stem cell (HSC) behaviour and, in particular, stem cell dormancy and self-renewal. While these processes have been linked to a number of different stromal cell types and signalling pathways, it is currently unclear whether BM has a homogenous architecture devoid of structural and functional partitions. Here, we show with genetic labelling techniques, high-resolution imaging and functional experiments in mice that the periphery of the adult BM cavity harbours previously unrecognized compartments with distinct properties. These units, which we have termed hemospheres, were composed of endothelial, haematopoietic and mesenchymal cells, were enriched in CD150+ CD48- putative HSCs, and enabled rapid haematopoietic cell proliferation and clonal expansion. Inducible gene targeting of the receptor tyrosine kinase VEGFR2 in endothelial cells disrupted hemospheres and, concomitantly, reduced the number of CD150+ CD48- cells. Our results identify a previously unrecognized, vessel-associated BM compartment with a specific localization and properties distinct from the marrow cavity.

U2 - 10.1038/emboj.2012.308

DO - 10.1038/emboj.2012.308

M3 - Article

SN - 0261-4189

VL - 32

SP - 219

EP - 230

JO - EMBO Journal

JF - EMBO Journal

IS - 2

ER -

Identification of a clonally expanding haematopoietic compartment in bone marrow

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