title: Foxc1 is a critical regulator of haematopoietic stem/progenitor cell niche formation.
abstract: Haematopoietic stem and progenitor cells are maintained by special microenvironments known as niches in bone marrow. Many studies have identified diverse candidate cells that constitute niches for haematopoietic stem cells in the marrow, including osteoblasts, endothelial cells, Schwann cells, α-smooth muscle actin-expressing macrophages and mesenchymal progenitors such as CXC chemokine ligand (CXCL)12-abundant reticular (CAR) cells, stem cell factor-expressing cells, nestin-expressing cells and platelet-derived growth factor receptor-α (PDGFR-α)(+)Sca-1(+)CD45(-)Ter119(-) (PαS) cells. However, the molecular basis of the formation of the niches remains unclear. Here we find that the transcription factor Foxc1 is preferentially expressed in the adipo-osteogenic progenitor CAR cells essential for haematopoietic stem and progenitor cell maintenance in vivo in the developing and adult bone marrow. When Foxc1 was deleted in all marrow mesenchymal cells or CAR cells, from embryogenesis onwards, osteoblasts appeared normal, but haematopoietic stem and progenitor cells were markedly reduced and marrow cavities were occupied by adipocytes (yellow adipose marrow) with reduced CAR cells. Inducible deletion of Foxc1 in adult mice depleted haematopoietic stem and progenitor cells and reduced CXCL12 and stem cell factor expression in CAR cells but did not induce a change to yellow marrow. These data suggest a role for Foxc1 in inhibiting adipogenic processes in CAR progenitors. Foxc1 might also promote CAR cell development, upregulating CXCL12 and stem cell factor expression. This study identifies Foxc1 as a specific transcriptional regulator essential for development and maintenance of the mesenchymal niches for haematopoietic stem and progenitor cells.
authors.affiliation: 1] Department of Immunobiology and Hematology, Institute for Frontier Medical Sciences, Kyoto University, Japan [2] Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST), 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Omatsu
authors.affiliation: 1] Department of Immunobiology and Hematology, Institute for Frontier Medical Sciences, Kyoto University, Japan [2] Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST), 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Masanari
authors.initials: M
authors.lastname: Seike
authors.affiliation: 1] Department of Immunobiology and Hematology, Institute for Frontier Medical Sciences, Kyoto University, Japan [2] Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST), 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Sugiyama
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kume
authors.affiliation: 1] Department of Immunobiology and Hematology, Institute for Frontier Medical Sciences, Kyoto University, Japan [2] Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST), 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nagasawa
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002452:Cell Count; D002454:Cell Differentiation; D054377:Chemokine CXCL12 / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D019089:Stem Cell Factor / Q000378:metabolism; D055153:Stem Cell Niche / Q000502:physiology*
chemical_list: D054377:Chemokine CXCL12; D051858:Forkhead Transcription Factors; C112890:Foxc1 protein, mouse; D019089:Stem Cell Factor