title: Extracellular matrix protein tenascin-C is required in the bone marrow microenvironment primed for hematopoietic regeneration.
abstract: The BM microenvironment is required for the maintenance, proliferation, and mobilization of hematopoietic stem and progenitor cells (HSPCs), both during steady-state conditions and hematopoietic recovery after myeloablation. The ECM meshwork has long been recognized as a major anatomical component of the BM microenvironment; however, the molecular signatures and functions of the ECM to support HSPCs are poorly understood. Of the many ECM proteins, the expression of tenascin-C (TN-C) was found to be dramatically up-regulated during hematopoietic recovery after myeloablation. The TN-C gene was predominantly expressed in stromal cells and endothelial cells, known as BM niche cells, supporting the function of HSPCs. Mice lacking TN-C (TN-C(-/-)) mice showed normal steady-state hematopoiesis; however, they failed to reconstitute hematopoiesis after BM ablation and showed high lethality. The capacity to support transplanted wild-type hematopoietic cells to regenerate hematopoiesis was reduced in TN-C(-/-) recipient mice. In vitro culture on a TN-C substratum promoted the proliferation of HSPCs in an integrin α9-dependent manner and up-regulated the expression of the cyclins (cyclinD1 and cyclinE1) and down-regulated the expression of the cyclin-dependent kinase inhibitors (p57(Kip2), p21(Cip1), p16(Ink4a)). These results identify TN-C as a critical component of the BM microenvironment that is required for hematopoietic regeneration.
authors.affiliation: Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Nakamura-Ishizu
authors.forename: Yuji
authors.initials: Y
authors.lastname: Okuno
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Omatsu
authors.forename: Keisuke
authors.initials: K
authors.lastname: Okabe
authors.forename: Junko
authors.initials: J
authors.lastname: Morimoto
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Uede
authors.forename: Takashi
authors.initials: T
authors.lastname: Nagasawa
authors.forename: Toshio
authors.initials: T
authors.lastname: Suda
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kubota
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D001854:Bone Marrow Cells / Q000166:cytology* / Q000378:metabolism; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D017353:Gene Deletion; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D039001:Integrin alpha Chains / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism; D019063:Tenascin / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D014916:Whole-Body Irradiation
chemical_list: D039001:Integrin alpha Chains; D012333:RNA, Messenger; D019063:Tenascin; C084613:integrin alpha9; D005472:Fluorouracil