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Journal of nanobiotechnology
Jun 12, 2023;21 (1): 189.

Exosomal miR-125b-5p derived from adipose-derived mesenchymal stem cells enhance diabetic hindlimb ischemia repair via targeting alkaline ceramidase 2.

Jiahe Guo, Xiaofan Yang, Jing Chen, Cheng Wang, Yue Sun, Chengqi Yan, Sen Ren, Hewei Xiong, Kaituo Xiang, Maojie Zhang, Chengcheng Li, Guoyong Jiang, Xuejiao Xiang, Gui Wan, Tao Jiang, Yu Kang, Xiang Xu, Zhenbing Chen, Wenqing Li
Author Information
  1. Jiahe Guo: Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  2. Xiaofan Yang: Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  3. Jing Chen: Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  4. Cheng Wang: Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  5. Yue Sun: The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, 430022, China.
  6. Chengqi Yan: Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  7. Sen Ren: Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
  8. Hewei Xiong: Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  9. Kaituo Xiang: Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  10. Maojie Zhang: Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  11. Chengcheng Li: Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  12. Guoyong Jiang: Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  13. Xuejiao Xiang: Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  14. Gui Wan: Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  15. Tao Jiang: Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  16. Yu Kang: Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  17. Xiang Xu: Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  18. Zhenbing Chen: Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. zbchen@hust.edu.cn.
  19. Wenqing Li: Department of Hand and Foot Surgery, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518052, China. limo1997@163.com.
PMID: 37308908 DOI: 10.1186/s12951-023-01954-8

Abstract

INTRODUCTION: Ischemic diseases caused by diabetes continue to pose a major health challenge and effective treatments are in high demand. Mesenchymal stem cells (MSCs) derived exosomes have aroused broad attention as a cell-free treatment for ischemic diseases. However, the efficacy of exosomes from adipose-derived mesenchymal stem cells (ADSC-Exos) in treating diabetic lower limb ischemic injury remains unclear.
METHODS: Exosomes were isolated from ADSCs culture supernatants by differential ultracentrifugation and their effect on C2C12 cells and HUVECs was assessed by EdU, Transwell, and in vitro tube formation assays separately. The recovery of limb function after ADSC-Exos treatment was evaluated by Laser-Doppler perfusion imaging, limb function score, and histological analysis. Subsequently, miRNA sequencing and rescue experiments were performed to figure out the responsible miRNA for the protective role of ADSC-Exos on diabetic hindlimb ischemic injury. Finally, the direct target of miRNA in C2C12 cells was confirmed by bioinformatic analysis and dual-luciferase report gene assay.
RESULTS: ADSC-Exos have the potential to promote proliferation and migration of C2C12 cells and to promote HUVECs angiogenesis. In vivo experiments have shown that ADSC-Exos can protect ischemic skeletal muscle, promote the repair of muscle injury, and accelerate vascular regeneration. Combined with bioinformatics analysis, miR-125b-5p may be a key molecule in this process. Transfer of miR-125b-5p into C2C12 cells was able to promote cell proliferation and migration by suppressing ACER2 overexpression.
CONCLUSION: The findings revealed that miR-125b-5p derived from ADSC-Exos may play a critical role in ischemic muscle reparation by targeting ACER2. In conclusion, our study may provide new insights into the potential of ADSC-Exos as a treatment option for diabetic lower limb ischemia.

Keywords

Adipose-derived mesenchymal stem cells Alkaline ceramidase 2 Bioinformatics analysis Exosomes Hindlimb ischemia miR-125b-5p

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Grants

  1. YCJJ202201037/Fundamental Research funds for the Central Universities
  2. 82101473/National Natural Science Foundation of China
  3. JCYJ20210324112212034/Shenzhen Basic Research Project

MeSH Term

Animals
Alkaline Ceramidase
Mesenchymal Stem Cells
Diabetes Mellitus
Ischemia
Hindlimb

Chemicals

Alkaline Ceramidase
Journal Article
Article has an altmetric score of 4

Word Cloud

Created with Highcharts 10.0.0cellsADSC-ExosischemicmiR-125b-5pstemdiabeticlimbC2C12analysispromotederivedtreatmentmesenchymalinjurymiRNAmusclemayischemiadiseasesexosomesadipose-derivedlowerExosomesHUVECsfunctionexperimentsrolehindlimbpotentialproliferationmigrationrepairACER2targetingceramidase2INTRODUCTION:IschemiccauseddiabetescontinueposemajorhealthchallengeeffectivetreatmentshighdemandMesenchymalMSCsarousedbroadattentioncell-freeHoweverefficacytreatingremainsunclearMETHODS:isolatedADSCsculturesupernatantsdifferentialultracentrifugationeffectassessedEdUTranswellvitrotubeformationassaysseparatelyrecoveryevaluatedLaser-DopplerperfusionimagingscorehistologicalSubsequentlysequencingrescueperformedfigureresponsibleprotectiveFinallydirecttargetconfirmedbioinformaticdual-luciferasereportgeneassayRESULTS:angiogenesisvivoshowncanprotectskeletalacceleratevascularregenerationCombinedbioinformaticskeymoleculeprocessTransferablecellsuppressingoverexpressionCONCLUSION:findingsrevealedplaycriticalreparationconclusionstudyprovidenewinsightsoptionExosomalenhanceviaalkalineAdipose-derivedAlkalineBioinformaticsHindlimb

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