PMID- 35151688 OWN - NLM STAT- MEDLINE DCOM- 20220415 LR - 20220531 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 298 IP - 3 DP - 2022 Mar TI - Exosomal miR-673-5p from fibroblasts promotes Schwann cell-mediated peripheral neuron myelination by targeting the TSC2/mTORC1/SREBP2 axis. PG - 101718 LID - S0021-9258(22)00158-2 [pii] LID - 10.1016/j.jbc.2022.101718 [doi] LID - 101718 AB - Peripheral myelination is a complicated process, wherein Schwann cells (SCs) promote the formation of the myelin sheath around the axons of peripheral neurons. Fibroblasts are the second resident cells in the peripheral nerves; however, the precise function of fibroblasts in SC-mediated myelination has rarely been examined. Here, we show that exosomes derived from fibroblasts boost myelination-related gene expression in SCs. We used exosome sequencing, together with bioinformatic analysis, to demonstrate that exosomal microRNA miR-673-5p is capable of stimulating myelin gene expression in SCs. Subsequent functional studies revealed that miR-673-5p targets the regulator of mechanistic target of the rapamycin (mTOR) complex 1 (mTORC1) tuberous sclerosis complex 2 in SCs, leading to the activation of downstream signaling pathways including mTORC1 and sterol-regulatory element binding protein 2. In vivo experiments further confirmed that miR-673-5p activates the tuberous sclerosis complex 2/mTORC1/sterol-regulatory element binding protein 2 axis, thus promoting the synthesis of cholesterol and related lipids and subsequently accelerating myelin sheath maturation in peripheral nerves. Overall, our findings revealed exosome-mediated cross talk between fibroblasts and SCs that plays a pivotal role in peripheral myelination. We propose that exosomes derived from fibroblasts and miR-673-5p might be useful for promoting peripheral myelination in translational medicine. CI - Copyright (c) 2022 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Zhao, Yahong AU - Zhao Y AD - Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education; Co-innovation Center of Neurogeneration; NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China. Electronic address: zhaoyh108@ntu.edu.cn. FAU - Liang, Yunyun AU - Liang Y AD - Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education; Co-innovation Center of Neurogeneration; NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China. FAU - Xu, Zhixin AU - Xu Z AD - Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education; Co-innovation Center of Neurogeneration; NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China. FAU - Liu, Jina AU - Liu J AD - Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education; Co-innovation Center of Neurogeneration; NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China. FAU - Liu, Xiaoyu AU - Liu X AD - Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education; Co-innovation Center of Neurogeneration; NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China. FAU - Ma, Jinyu AU - Ma J AD - Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education; Co-innovation Center of Neurogeneration; NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China. FAU - Sun, Cheng AU - Sun C AD - Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education; Co-innovation Center of Neurogeneration; NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China. Electronic address: suncheng1975@ntu.edu.cn. FAU - Yang, Yumin AU - Yang Y AD - Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education; Co-innovation Center of Neurogeneration; NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China. Electronic address: yangym@ntu.edu.cn. LA - eng PT - Journal Article DEP - 20220211 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (MicroRNAs) RN - 0 (SREBF2 protein, human) RN - 0 (Sterol Regulatory Element Binding Protein 2) RN - 0 (Sterols) RN - 0 (TSC2 protein, human) RN - 0 (Tuberous Sclerosis Complex 2 Protein) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) SB - IM MH - Exosomes/genetics/metabolism MH - Fibroblasts/metabolism MH - Humans MH - *Mechanistic Target of Rapamycin Complex 1/genetics/metabolism MH - *MicroRNAs/genetics/metabolism MH - *Myelin Sheath/metabolism MH - *Schwann Cells/metabolism MH - *Sterol Regulatory Element Binding Protein 2/metabolism MH - Sterols/metabolism MH - *Tuberous Sclerosis/metabolism MH - *Tuberous Sclerosis Complex 2 Protein/genetics/metabolism PMC - PMC8908274 OTO - NOTNLM OT - Schwann cells OT - exosomes OT - fibroblasts OT - lipid synthesis OT - myelination OT - peripheral nerve regeneration COIS- Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. EDAT- 2022/02/14 06:00 MHDA- 2022/04/16 06:00 PMCR- 2022/02/11 CRDT- 2022/02/13 20:28 PHST- 2021/10/22 00:00 [received] PHST- 2022/02/06 00:00 [revised] PHST- 2022/02/07 00:00 [accepted] PHST- 2022/02/14 06:00 [pubmed] PHST- 2022/04/16 06:00 [medline] PHST- 2022/02/13 20:28 [entrez] PHST- 2022/02/11 00:00 [pmc-release] AID - S0021-9258(22)00158-2 [pii] AID - 101718 [pii] AID - 10.1016/j.jbc.2022.101718 [doi] PST - ppublish SO - J Biol Chem. 2022 Mar;298(3):101718. doi: 10.1016/j.jbc.2022.101718. Epub 2022 Feb 11.