title: TGF-β1 signaling and Krüppel-like factor 10 regulate bone marrow-derived proangiogenic cell differentiation, function, and neovascularization.
abstract: Emerging evidence demonstrates that proangiogenic cells (PACs) originate from the BM and are capable of being recruited to sites of ischemic injury where they contribute to neovascularization. We previously determined that among hematopoietic progenitor stem cells, common myeloid progenitors (CMPs) and granulocyte-macrophage progenitor cells (GMPs) differentiate into PACs and possess robust angiogenic activity under ischemic conditions. Herein, we report that a TGF-β1-responsive Krüppel- like factor, KLF10, is strongly expressed in PACs derived from CMPs and GMPs, ∼ 60-fold higher than in progenitors lacking PAC markers. KLF10(-/-) mice present with marked defects in PAC differentiation, function, TGF-β responsiveness, and impaired blood flow recovery after hindlimb ischemia, an effect rescued by wild-type PACs, but not KLF10(-/-) PACs. Overexpression studies revealed that KLF10 could rescue PAC formation from TGF-β1(+/-) CMPs and GMPs. Mechanistically, KLF10 targets the VEGFR2 promoter in PACs which may underlie the observed effects. These findings may be clinically relevant because KLF10 expression was also found to be significantly reduced in PACs from patients with peripheral artery disease. Collectively, these observations identify TGF-β1 signaling and KLF10 as key regulators of functional PACs derived from CMPs and GMPs and may provide a therapeutic target during cardiovascular ischemic states.
authors.affiliation: Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Akm Khyrul
authors.initials: AK
authors.lastname: Wara
authors.forename: ShiYin
authors.initials: S
authors.lastname: Foo
authors.forename: Kevin
authors.initials: K
authors.lastname: Croce
authors.forename: Xinghui
authors.initials: X
authors.lastname: Sun
authors.forename: Basak
authors.initials: B
authors.lastname: Icli
authors.forename: Yevgenia
authors.initials: Y
authors.lastname: Tesmenitsky
authors.forename: Fehim
authors.initials: F
authors.lastname: Esen
authors.forename: Jung-Soo
authors.initials: JS
authors.lastname: Lee
authors.forename: Malayannan
authors.initials: M
authors.lastname: Subramaniam
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Spelsberg
authors.forename: Eli I
authors.initials: EI
authors.lastname: Lev
authors.forename: Dorit
authors.initials: D
authors.lastname: Leshem-Lev
authors.forename: Reena L
authors.initials: RL
authors.lastname: Pande
authors.forename: Mark A
authors.initials: MA
authors.lastname: Creager
authors.forename: Anthony
authors.initials: A
authors.lastname: Rosenzweig
authors.forename: Mark W
authors.initials: MW
authors.lastname: Feinberg
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000502:physiology*; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000235:genetics; D051765:Early Growth Response Transcription Factors / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D055014:Granulocyte-Macrophage Progenitor Cells / Q000166:cytology / Q000502:physiology; D006614:Hindlimb; D007511:Ischemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000502:physiology; D018919:Neovascularization, Physiologic; D058729:Peripheral Arterial Disease / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D012039:Regional Blood Flow; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D051765:Early Growth Response Transcription Factors; C569958:KLF10 protein, mouse; D051741:Kruppel-Like Transcription Factors; D012333:RNA, Messenger; C499308:Rag2 protein, mouse; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D040301:Vascular Endothelial Growth Factor Receptor-2