title: Pivotal role of lnk adaptor protein in endothelial progenitor cell biology for vascular regeneration.
abstract: Despite the fact that endothelial progenitor cells (EPCs) are important for postnatal neovascularization, their origins, differentiation, and modulators are not clear. Here, we demonstrate that Lnk, a negative regulator of hematopoietic stem cell proliferation, controls endothelial commitment of c-kit(+)/Sca-1(+)/Lineage(-) (KSL) subpopulations of bone marrow cells. The results of EPC colony-forming assays reveal that small (primitive) EPC colony formation by CD34(-) KSLs and large (definitive) EPC colony formation by CD34((dim)) KSLs are more robust in lnk(-/-) mice. In hindlimb ischemia, perfusion recovery is augmented in lnk(-/-) mice through enhanced proliferation and mobilization of EPCs via c-Kit/stem cell factor. We found that Lnk-deficient EPCs are more potent actors than resident cells in hindlimb perfusion recovery and ischemic neovascularization, mainly via the activity of bone marrow-EPCs. Similarly, lnk(-/-) mice show augmented retinal neovascularization and astrocyte network maturation without an increase in indicators of pathogenic angiogenesis in an in vivo model of retinopathy. Taken together, our results provide strong evidence that Lnk regulates bone marrow-EPC kinetics in vascular regeneration. Selective targeting of Lnk may be a safe and effective strategy to augment therapeutic neovascularization by EPC transplantation.
authors.affiliation: Department of Regenerative Medicine Science, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Sang-Mo
authors.initials: SM
authors.lastname: Kwon
authors.forename: Takahiro
authors.initials: T
authors.lastname: Suzuki
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Kawamoto
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ii
authors.forename: Masamichi
authors.initials: M
authors.lastname: Eguchi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Akimaru
authors.forename: Mika
authors.initials: M
authors.lastname: Wada
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Haruchika
authors.initials: H
authors.lastname: Masuda
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Hiromi
authors.initials: H
authors.lastname: Nishimura
authors.forename: Kenji
authors.initials: K
authors.lastname: Kawai
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takaki
authors.forename: Takayuki
authors.initials: T
authors.lastname: Asahara