title: Selective Interference Targeting of Lnk in Umbilical Cord-Derived Late Endothelial Progenitor Cells Improves Vascular Repair, Following Hind Limb Ischemic Injury, via Regulation of JAK2/STAT3 Signaling.
abstract: The Lnk adaptor protein is a strong negative regulator that affects self-renewal of hematopoietic stem cells and vascular repair in injured tissues. However, the signaling mechanisms through which these proteins influence the vascular regeneration function of endothelial progenitor cells (EPCs) remain unknown. In this study, we investigated the effect of Lnk-targeted small interfering RNA (si-lnk) on the clonogenic proliferative potential and vascular regenerative function of EPCs and the activation of the JAK/STAT3 signaling pathway. Treatment with stem cell factor (SCF) increased the clonogenic proliferation of si-lnk EPCs. Importantly, activation of the JAK2/STAT3 pathway was enhanced in SCF-sensitized si-lnk EPCs. In a hind limb model of ischemia, transplantation of si-lnk EPCs increased the blood flow ratio, capillary density, proliferation, and survival of transplanted cells, and the secretion of pivotal angiogenic cytokines at ischemic sites. These results provide strong evidence that si-lnk regulates the clonogenic proliferative potential of EPCs through the activation of the JAK2/STAT3 signaling pathway, thereby accelerating angiogenesis and promoting repair in injured hind limb ischemia. Stem Cells 2014;33:1490-1500.
authors.affiliation: Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, South Korea; Department of Biochemistry, School of Medicine, Soonchunhyang University, Cheonan, South Korea; Laboratory for Vascular Medicine and Stem Cell Biology, Department of Physiology, School of Medicine, Pusan National University, Medical Research Institute, School of Medicine, Pusan National University, Yangsan, Gyeongnam, South Korea.
authors.forename: Sang Hun
authors.initials: SH
authors.lastname: Lee
authors.forename: Kyeung Bin
authors.initials: KB
authors.lastname: Lee
authors.forename: Jun Hee
authors.initials: JH
authors.lastname: Lee
authors.forename: Songhwa
authors.initials: S
authors.lastname: Kang
authors.forename: Hwi Gon
authors.initials: HG
authors.lastname: Kim
authors.forename: Takayuki
authors.initials: T
authors.lastname: Asahara
authors.forename: Sang Mo
authors.initials: SM
authors.lastname: Kwon
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D000066673:Cell Self Renewal / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D066026:Endothelial Progenitor Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000637:transplantation; D018390:Gene Targeting; D006614:Hindlimb / Q000098:blood supply* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007511:Ischemia / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D053614:Janus Kinase 2 / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019089:Stem Cell Factor / Q000494:pharmacology; D014470:Umbilical Cord / Q000166:cytology*; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; C490777:Lnk protein, mouse; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D019089:Stem Cell Factor; D042461:Vascular Endothelial Growth Factor A; D053614:Janus Kinase 2
keywords: Endothelial progenitor cells; JAK2/STAT3; Lnk; Neovascularization; Repopulation ability