1. Stowers Institute for Medical Research, 1000 E. 50th Street, Kansas City, Missouri 64110, USA
2. Department of Cardiology, Shanghai Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197, Rui Jin 2 Road, Shanghai 200025, China
3. Department of Microbiology and Immunology, and Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA
4. Department of Pathology and Laboratory Medicine, Kansas University Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160, USA
5. These authors contributed equally to this work.

Correspondence to: Ricardo A. Feldman³Linheng Li^1,4 Correspondence and requests for materials should be addressed to R.A.F. (Email: rfeldman@umaryland.edu) and L.L. (Email: lil@stowers-institute.org).

Abstract

Haematopoietic stem cell (HSC) niches, although proposed decades ago¹, have only recently been identified as separate osteoblastic and vascular microenvironments^{2, 3, 4, 5, 6}. Their interrelationships and interactions with HSCs in vivo remain largely unknown. Here we report the use of a newly developed ex vivo real-time imaging technology and immunoassaying to trace the homing of purified green-fluorescent-protein-expressing (GFP⁺) HSCs. We found that transplanted HSCs tended to home to the endosteum (an inner bone surface) in irradiated mice, but were randomly distributed and unstable in non-irradiated mice. Moreover, GFP⁺ HSCs were more frequently detected in the trabecular bone area compared with compact bone area, and this was validated by live imaging bioluminescence driven by the stem-cell-leukaemia (Scl) promoter–enhancer⁷. HSCs home to bone marrow through the vascular system. We found that the endosteum is well vascularized and that vasculature is frequently localized near N-cadherin⁺ pre-osteoblastic cells, a known niche component. By monitoring individual HSC behaviour using real-time imaging, we found that a portion of the homed HSCs underwent active division in the irradiated mice, coinciding with their expansion as measured by flow assay. Thus, in contrast to central marrow, the endosteum formed a special zone, which normally maintains HSCs but promotes their expansion in response to bone marrow damage.

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