Little is known about the formation of niches, local micro-environments required for stem-cell maintenance. Here we develop an in vivo assay for adult haematopoietic stem-cell (HSC) niche formation1,2. With this assay, we identified a population of progenitor cells with surface markers CD45-Tie2-αV+CD105+Thy1.1- (CD105+Thy1-) that, when sorted from 15.5 days post-coitum fetal bones and transplanted under the adult mouse kidney capsule, could recruit host-derived blood vessels, produce donor-derived ectopic bones through a cartilage intermediate and generate a marrow cavity populated by host-derived long-term reconstituting HSC (LT-HSC). In contrast, CD45-Tie2-αV+CD105+Thy1+ (CD105+Thy1+) fetal bone progenitors form bone that does not contain a marrow cavity. Suppressing expression of factors involved in endochondral ossification, such as osterix and vascular endothelial growth factor (VEGF), inhibited niche generation. CD105+Thy1- progenitor populations derived from regions of the fetal mandible or calvaria that do not undergo endochondral ossification formed only bone without marrow in our assay. Collectively, our data implicate endochondral ossification, bone formation that proceeds through a cartilage intermediate, as a requirement for adult HSC niche formation.
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We thank B. Péault for suggestions; L. Jerabek for laboratory management; C. Muscat for antibody production and conjugation;Y. Park, J. K. Lee and A. K. Bershad for technical support; and T. Serwold and L. Richie for advice and reading the manuscript. This study was supported in part by a USPHS National Institutes of Health (NIH) grant (2R01HL058770-08) and in part by a NIH grant (5R01CA086065-09), terminated by NIH Study Section, and in part by the Virginia and Daniel K. Ludwig Professorship to I.L.W. C.K.F.C. and C.A.L. are supported by an NIH Regenerative Medicine training grant. C.-C.C. is supported by an NIH Pathway to Independence award (5K99HL087936-02). D.L.K. is supported by an NIH Career Development award (K08-HL076335) and a Hope Street Kids research award, K. W. and C. J. K. are supported by NIH grants (1R01HL074267-01 and 1R01NS052830-01).
Author Contributions C.K.F.C. initiated the project and, with C.-C.C. and I.L.W., supervised the study, C.K.F.C., C.-C.C., C.A.L., D.L.K., J.B.K. and I.L.W. conceived and designed the experiments. C.K.F.C., C.-C.C., C.A.L., D.L.K., J.B.K., A.T.D. and K.W. performed the experiments. C.K.F.C., C.-C.C., C.A.L., D.L.K., J.B.K., A.T.D., J.A.H., C.J.K., and I.L.W. analysed the data. C.K.F.C., C.-C.C., I.L.W., C.J.K. and J.A.H. contributed reagents/materials/analysis tools. C.K.F.C., C.-C.C., C.A.L., D.L.K. and I.L.W. prepared the manuscript.
This file contains Supplementary Methods, Supplementary Tables 1- 2, Supplementary Figures S1-S5 and Supplementary References. (This file was re-uploaded on December 12th, 2008 to incorporate the Supplementary Methods, Supplementary Tables 1-2 and Supplementary References missed from the original file).