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Endothelial and perivascular cells maintain haematopoietic stem cells

Abstract

Several cell types have been proposed to create niches for haematopoietic stem cells (HSCs). However, the expression patterns of HSC maintenance factors have not been systematically studied and no such factor has been conditionally deleted from any candidate niche cell. Thus, the cellular sources of these factors are undetermined. Stem cell factor (SCF; also known as KITL) is a key niche component that maintains HSCs. Here, using Scfgfp knock-in mice, we found that Scf was primarily expressed by perivascular cells throughout the bone marrow. HSC frequency and function were not affected when Scf was conditionally deleted from haematopoietic cells, osteoblasts, nestin-cre- or nestin-creER-expressing cells. However, HSCs were depleted from bone marrow when Scf was deleted from endothelial cells or leptin receptor (Lepr)-expressing perivascular stromal cells. Most HSCs were lost when Scf was deleted from both endothelial and Lepr-expressing perivascular cells. Thus, HSCs reside in a perivascular niche in which multiple cell types express factors that promote HSC maintenance.

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Figure 1: Scf gfp is a strong loss-of-function allele and Scf is primarily expressed by perivascular cells in the bone marrow.
Figure 2: Scf is required for adult HSC maintenance.
Figure 3: SCF from haematopoietic cells, osteoblasts and nestin-Cre-expressing stromal cells is not required for HSC maintenance.
Figure 4: Deletion of Scf from endothelial cells depletes HSCs.
Figure 5: Deletion of Scf from Lepr-cre -expressing perivascular stromal cells depletes HSCs in the bone marrow.

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Gene Expression Omnibus

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The microarray data were deposited in the Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) under accession number GSE33158.

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Acknowledgements

This work was supported by the Howard Hughes Medical Institute (HHMI) and the National Heart, Lung and Blood Institute (5R01HL097760). L.D. was supported by a Helen Hay Whitney Foundation Fellowship and by the HHMI. G.E. was supported by the National Institute of Aging (R01AG040209) and NYSTEM. We thank M. White and D. Adams for flow cytometry, E. Hughes at the UM transgenic core for helping to generate Scfgfp and Scffl mice, M. Purkey for technical assistance, J. Peyer and M. Lim for discussion, and C. Mountford, S. Grove and R. Coolon for managing the mouse colony. This work was initiated in the Life Sciences Institute at the University of Michigan then completed at Children’s Research Institute at UT Southwestern.

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L.D. performed all of the experiments. T.L.S. helped to design and generate the Scffl and Scfgfp mice. G.E. generated the nestin-Cherry transgenic mice. L.D. and S.J.M. 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., Saunders, T., Enikolopov, G. et al. Endothelial and perivascular cells maintain haematopoietic stem cells. Nature 481, 457–462 (2012). https://doi.org/10.1038/nature10783

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