title: Klf5 controls bone marrow homing of stem cells and progenitors through Rab5-mediated β1/β2-integrin trafficking.
abstract: Krüppel-like factor 5 regulates pluripotent stem cell self-renewal, but its role in somatic stem cells is unknown. Here we show that Krüppel-like factor 5-deficient haematopoietic stem cells and progenitors fail to engraft after transplantation. This haematopoietic stem cell and progenitor defect is associated with impaired bone marrow homing and lodging and decreased retention in bone marrow, and with decreased adhesion to fibronectin and expression of membrane-bound β1/β2-integrins. In vivo-inducible gain-of-function of Krüppel-like factor 5 in haematopoietic stem cells increases haematopoietic stem cell and progenitor adhesion. The expression of Rab5 family members, mediators of β1/β2-integrin recycling in the early endosome, is decreased in Klf5(Δ/Δ) haematopoietic stem cells and progenitors. Krüppel-like factor 5 binds directly to the promoter of Rab5a/b, and overexpression of Rab5b rescues the expression of activated β1/β2-integrins, adhesion and bone marrow homing of Klf5(Δ/Δ) haematopoietic stem cells and progenitors. Altogether, these data indicate that Krüppel-like factor 5 is indispensable for adhesion, homing, lodging and retention of haematopoietic stem cells and progenitors in the bone marrow through Rab5-dependent post-translational regulation of β1/β2 integrins.
authors.affiliation: Hoxworth Blood Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0055, USA.
authors.forename: E
authors.initials: E
authors.lastname: Taniguchi Ishikawa
authors.forename: K H
authors.initials: KH
authors.lastname: Chang
authors.forename: R
authors.initials: R
authors.lastname: Nayak
authors.forename: H A
authors.initials: HA
authors.lastname: Olsson
authors.forename: A M
authors.initials: AM
authors.lastname: Ficker
authors.forename: S K
authors.initials: SK
authors.lastname: Dunn
authors.forename: M N
authors.initials: MN
authors.lastname: Madhu
authors.forename: A
authors.initials: A
authors.lastname: Sengupta
authors.forename: J A
authors.initials: JA
authors.lastname: Whitsett
authors.forename: H L
authors.initials: HL
authors.lastname: Grimes
authors.forename: J A
authors.initials: JA
authors.lastname: Cancelas
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D018821:CD18 Antigens / Q000378:metabolism*; D002448:Cell Adhesion; D005353:Fibronectins / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics; D013234:Stem Cells / Q000166:cytology*; D020696:rab5 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018821:CD18 Antigens; D005353:Fibronectins; D019012:Integrin beta1; C118391:Klf5 protein, mouse; D051741:Kruppel-Like Transcription Factors; D012333:RNA, Messenger; D020696:rab5 GTP-Binding Proteins
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