Netrin-1-Induced Stem Cell Bioactivity Contributes to the Regeneration of Injured Tissues via the Lipid Raft-Dependent Integrin alpha 6 beta 4 Signaling Pathway
- Authors
- Lee, Soo Sang; Lee, Sei-Jung; Lee, Sang Hun; Ryu, Jung Min; Lim, Hyeon Su; Kim, Jun Sung; Song, Eun Ju; Jung, Young Hyun; Lee, Hyun Jik; Kim, Chung Hun; Han, Ho Jae
- Issue Date
- 24-Nov-2016
- Publisher
- Nature Publishing Group
- Keywords
- Netrin-1; Integrinα6β4; hUCB-MSCs; Stem cell therapy
- Citation
- Scientific Reports, v.6
- Journal Title
- Scientific Reports
- Volume
- 6
- URI
- https://scholarworks.bwise.kr/sch/handle/2021.sw.sch/8597
- DOI
- 10.1038/srep37526
- ISSN
- 2045-2322
- 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 In alpha 6 beta 4 coupled with c-Src. Ntn-1 induced the recruitment of NADPH oxidases and Rac1 into membrane lipid rafts to facilitate ROS production. The In alpha 6 beta 4 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 In alpha 6 beta 4 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 In alpha 6 beta 4 signaling pathway.
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Collections - College of Medicine > Department of Biochemistry > 1. Journal Articles
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