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Sci Rep. 2016 Nov 24;6:37526. doi: 10.1038/srep37526.

Netrin-1-Induced Stem Cell Bioactivity Contributes to the Regeneration of Injured Tissues via the Lipid Raft-Dependent Integrin α6β4 Signaling Pathway.

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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.
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.
Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, Korea.
Department of Veterinary Physiology, College of Veterinary Medicine, Chonnam National University, Gwangju, Republic of Korea.


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.

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