title: Endochondral ossification is required for haematopoietic stem-cell niche formation.
abstract: 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 formation. With this assay, we identified a population of progenitor cells with surface markers CD45(-)Tie2(-)alpha(V)(+)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(-)alpha(V)(+)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.
authors.affiliation: Department of Pathology, Developmental Biology and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, California, USA. chazchan@stanford.edu
authors.forename: Charles K F
authors.initials: CK
authors.lastname: Chan
authors.forename: Ching-Cheng
authors.initials: CC
authors.lastname: Chen
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Luppen
authors.forename: Jae-Beom
authors.initials: JB
authors.lastname: Kim
authors.forename: Anthony T
authors.initials: AT
authors.lastname: DeBoer
authors.forename: Kevin
authors.initials: K
authors.lastname: Wei
authors.forename: Jill A
authors.initials: JA
authors.lastname: Helms
authors.forename: Calvin J
authors.initials: CJ
authors.lastname: Kuo
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kraft
authors.forename: Irving L
authors.initials: IL
authors.lastname: Weissman
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002356:Cartilage / Q000166:cytology* / Q000196:embryology; D002828:Choristoma; D005333:Fetus / Q000166:cytology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D008334:Mandible / Q000166:cytology / Q000196:embryology; D051379:Mice; D008810:Mice, Inbred C57BL; D010012:Osteogenesis / Q000502:physiology*; D012886:Skull / Q000166:cytology / Q000196:embryology; D000076182:Sp7 Transcription Factor; D055153:Stem Cell Niche / Q000166:cytology* / Q000502:physiology*; D018800:Thy-1 Antigens / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D018800:Thy-1 Antigens; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse