title: Netrin-1-Induced Stem Cell Bioactivity Contributes to the Regeneration of Injured Tissues via the Lipid Raft-Dependent Integrin α6β4 Signaling Pathway.
abstract: Netrin-1 (Ntn-1) is a multifunctional neuronal signaling molecule; however, its physiological significance, which improves the tissue-regeneration capacity of stem cells, has not been characterized. In the present study, we investigate the mechanism by which Ntn-1 promotes the proliferation of hUCB-MSCs with regard to the regeneration of injured tissues. We found that Ntn-1 induces the proliferation of hUCB-MSCs mainly via Inα6β4 coupled with c-Src. Ntn-1 induced the recruitment of NADPH oxidases and Rac1 into membrane lipid rafts to facilitate ROS production. The Inα6β4 signaling of Ntn-1 through ROS production is uniquely mediated by the activation of SP1 for cell cycle progression and the transcriptional occupancy of SP1 on the VEGF promoter. Moreover, Ntn-1 has the ability to induce the F-actin reorganization of hUCB-MSCs via the Inα6β4 signaling pathway. In an in vivo model, transplantation of hUCB-MSCs pre-treated with Ntn-1 enhanced the skin wound healing process, where relatively more angiogenesis was detected. The potential effect of Ntn-1 on angiogenesis is further verified by the mouse hindlimb ischemia model, where the pre-activation of hUCB-MSCs with Ntn-1 significantly improved vascular regeneration. These results demonstrate that Ntn-1 plays an important role in the tissue regeneration process of hUCB-MSC via the lipid raft-mediated Inα6β4 signaling pathway.
authors.affiliation: Department of plastic and reconstructive surgery, Bundang CHA Medical Center, Yatap-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, Korea.|SKY plastic surgery clinic, 4F, 826-23, Yeoksam-dong, Gangnam-gu, Seoul, Korea.
authors.forename: Soo Sang
authors.initials: SS
authors.lastname: Lee
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science and BK21 PLUS Program for Creative Veterinary Science Research Center, Seoul National University, Seoul 08826, Korea.
authors.forename: Sei-Jung
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, Korea.
authors.forename: Sang Hun
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Ryu
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science and BK21 PLUS Program for Creative Veterinary Science Research Center, Seoul National University, Seoul 08826, Korea.
authors.forename: Hyeon Su
authors.initials: HS
authors.lastname: Lim
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science and BK21 PLUS Program for Creative Veterinary Science Research Center, Seoul National University, Seoul 08826, Korea.
authors.forename: Jun Sung
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science and BK21 PLUS Program for Creative Veterinary Science Research Center, Seoul National University, Seoul 08826, Korea.
authors.forename: Eun Ju
authors.initials: EJ
authors.lastname: Song
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science and BK21 PLUS Program for Creative Veterinary Science Research Center, Seoul National University, Seoul 08826, Korea.
authors.forename: Young Hyun
authors.initials: YH
authors.lastname: Jung
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science and BK21 PLUS Program for Creative Veterinary Science Research Center, Seoul National University, Seoul 08826, Korea.
authors.forename: Hyun Jik
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of plastic and reconstructive surgery, Bundang CHA Medical Center, Yatap-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, Korea.
authors.forename: Chung Hun
authors.initials: CH
authors.lastname: Kim
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science and BK21 PLUS Program for Creative Veterinary Science Research Center, Seoul National University, Seoul 08826, Korea.
authors.forename: Ho Jae
authors.initials: HJ
authors.lastname: Han
mesh_terms: D000199:Actins / Q000235:genetics; D000818:Animals; D001808:Blood Vessels / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics; D005312:Fetal Blood / Q000166:cytology / Q000378:metabolism; D006801:Humans; D039161:Integrin alpha6beta4 / Q000235:genetics*; D021962:Membrane Microdomains / Q000235:genetics / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation; D051379:Mice; D018919:Neovascularization, Physiologic / Q000235:genetics*; D000075388:Netrin-1 / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012038:Regeneration / Q000235:genetics*; D015398:Signal Transduction; D012867:Skin / Q000098:blood supply / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D014945:Wound Healing / Q000235:genetics
chemical_list: D000199:Actins; D039161:Integrin alpha6beta4; D042461:Vascular Endothelial Growth Factor A; D000075388:Netrin-1