Extracellular Vesicles from Hydroxycamptothecin Primed Umbilical Cord Stem Cells Enhance Anti-adhesion Potential for Treatment of Tendon Injury

Overview

Journal Stem Cell Res Ther

Publisher Biomed Central

Date 2020 Nov 26

PMID 33239069

Citations 15

Authors

Juehong Li

Zhixiao Yao

Hao Xiong

Haomin Cui

Xu Wang

Wei Zheng

Yun Qian

Cunyi Fan

Affiliations

Soon will be listed here.

Abstract

Background: Peritendinous fibrosis represents a fibrotic healing process that usually occurs after tendon injury or surgery. This worldwide challenge hampers the functional rehabilitation and the mobility of extremities. However, effective treatment is still lacking at present. The aim of our study was to explore the effect of extracellular vesicles derived from hydroxycamptothecin primed human umbilical cord stem cells (HCPT-EVs) on post-traumatic tendon adhesion.

Methods: Extracellular vesicles derived from unprimed human umbilical cord mesenchymal stem cells (Unprimed EVs) or HCPT-EVs were isolated and characterized. A rat model of Achilles tendon injury was used to confirm the anti-adhesion effect of HCPT-EVs and compared with that of Unprimed EVs in vivo. In vitro, the inhibitory effects of HCPT-EVs on fibroblast proliferation, viability, and myofibroblast differentiation upon TGF-β1 stimulation were compared with the effects of Unprimed EVs. For mechanistic analysis, the expression of endoplasmic reticulum stress (ERS)-associated proteins was examined among the effector cargos of HCPT-EVs and Unprimed EVs. The ERS antagonist salubrinal was used to determine the ERS dependence of the anti-adhesion effects of HCPT-EVs.

Results: There were no obvious differences between Unprimed EVs and HCPT-EVs in terms of morphology, particle size, characteristic protein expression, and cellular uptake. HCPT-EVs exhibited a fortified anti-adhesion effect after Achilles tendon injury compared with Unprimed EVs. Fibroblast proliferation and viability and myofibroblast differentiation were all inhibited by HCPT-EVs. These properties were superior for HCPT-EVs relative to Unprimed EVs. Mechanistically, HCPT-EVs contained more ERS-associated protein than Unprimed EVs and activated the ERS pathway in fibroblast to counteract myofibroblast differentiation.

Conclusion: This study demonstrates that HCPT-EVs show high anti-adhesion potential for the treatment of tendon injury by provoking ERS in fibroblasts. HCPT-EVs represent a promising strategy for clinical use in treating adhesion-related diseases.

Citing Articles

Nano-based drug delivery systems for active ingredients from traditional Chinese medicine: Harnessing the power of nanotechnology.

Zhang Y, Wang J, Wang M, Peng J, Kong X, Tian J Front Pharmacol. 2024; 15:1405252.

PMID: 38910887 PMC: 11190311. DOI: 10.3389/fphar.2024.1405252.

The Use of Extracellular Vesicles in Achilles Tendon Repair: A Systematic Review.

Kasula V, Padala V, Gupta N, Doyle D, Bagheri K, Anastasio A Biomedicines. 2024; 12(5).

PMID: 38790904 PMC: 11117955. DOI: 10.3390/biomedicines12050942.

Preclinical assessment of IL-1β primed human umbilical cord mesenchymal stem cells for tendon functional repair through TGF-β/IL-10 signaling.

Wang S, Yao Z, Chen L, Li J, Chen S, Fan C Heliyon. 2023; 9(11):e21411.

PMID: 37954299 PMC: 10638607. DOI: 10.1016/j.heliyon.2023.e21411.

Mesenchymal Stem Cell Conditioned Medium Modulates Inflammation in Tenocytes: Complete Conditioned Medium Has Superior Therapeutic Efficacy than Its Extracellular Vesicle Fraction.

Soukup R, Gerner I, Mohr T, Gueltekin S, Grillari J, Jenner F Int J Mol Sci. 2023; 24(13).

PMID: 37446034 PMC: 10342101. DOI: 10.3390/ijms241310857.

Mesenchymal stem cells: An efficient cell therapy for tendon repair (Review).

Jiang L, Lu J, Chen Y, Lyu K, Long L, Wang X Int J Mol Med. 2023; 52(2).

PMID: 37387410 PMC: 10373123. DOI: 10.3892/ijmm.2023.5273.

References

Yang Y, Pang M, Chen Y, Zhang L, Liu H, Tan J . Human umbilical cord mesenchymal stem cells to treat spinal cord injury in the early chronic phase: study protocol for a prospective, multicenter, randomized, placebo-controlled, single-blinded clinical trial. Neural Regen Res. 2020; 15(8):1532-1538. PMC: 7059580. DOI: 10.4103/1673-5374.274347. View

Zheng W, Qian Y, Chen S, Ruan H, Fan C . Rapamycin Protects Against Peritendinous Fibrosis Through Activation of Autophagy. Front Pharmacol. 2018; 9:402. PMC: 5921906. DOI: 10.3389/fphar.2018.00402. View

Shi Z, Wang Q, Jiang D . Extracellular vesicles from bone marrow-derived multipotent mesenchymal stromal cells regulate inflammation and enhance tendon healing. J Transl Med. 2019; 17(1):211. PMC: 6593555. DOI: 10.1186/s12967-019-1960-x. View

Berglund M, Hildebrand K, Zhang M, Hart D, Wiig M . Neuropeptide, mast cell, and myofibroblast expression after rabbit deep flexor tendon repair. J Hand Surg Am. 2010; 35(11):1842-9. DOI: 10.1016/j.jhsa.2010.06.031. View

Raikin S, Garras D, Krapchev P . Achilles tendon injuries in a United States population. Foot Ankle Int. 2013; 34(4):475-80. DOI: 10.1177/1071100713477621. View

Wang Z, Maruyama K, Sakisaka Y, Suzuki S, Tada H, Suto M . Cyclic Stretch Force Induces Periodontal Ligament Cells to Secrete Exosomes That Suppress IL-1β Production Through the Inhibition of the NF-κB Signaling Pathway in Macrophages. Front Immunol. 2019; 10:1310. PMC: 6595474. DOI: 10.3389/fimmu.2019.01310. View

Yanez-Mo M, Siljander P, Andreu Z, Bedina Zavec A, Borras F, Buzas E . Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles. 2015; 4:27066. PMC: 4433489. DOI: 10.3402/jev.v4.27066. View

Zhu L, Tian T, Wang J, He J, Chen T, Pan M . Hypoxia-elicited mesenchymal stem cell-derived exosomes facilitates cardiac repair through miR-125b-mediated prevention of cell death in myocardial infarction. Theranostics. 2019; 8(22):6163-6177. PMC: 6299684. DOI: 10.7150/thno.28021. View

Kim Y, Yoo S, Park H, Lim H, Kim Y, Lee S . Exosomes derived from human umbilical cord blood mesenchymal stem cells stimulates rejuvenation of human skin. Biochem Biophys Res Commun. 2017; 493(2):1102-1108. DOI: 10.1016/j.bbrc.2017.09.056. View

10.

Chen S, Tang Y, Liu Y, Zhang P, Lv L, Zhang X . Exosomes derived from miR-375-overexpressing human adipose mesenchymal stem cells promote bone regeneration. Cell Prolif. 2019; 52(5):e12669. PMC: 6797519. DOI: 10.1111/cpr.12669. View

11.

Zhang L, Liu H, Xu K, Ling Z, Huang Y, Hu Q . Hypoxia preconditioned renal tubular epithelial cell-derived extracellular vesicles alleviate renal ischaemia-reperfusion injury mediated by the HIF-1α/Rab22 pathway and potentially affected by microRNAs. Int J Biol Sci. 2019; 15(6):1161-1176. PMC: 6567810. DOI: 10.7150/ijbs.32004. View

12.

Shen H, Yoneda S, Abu-Amer Y, Guilak F, Gelberman R . Stem cell-derived extracellular vesicles attenuate the early inflammatory response after tendon injury and repair. J Orthop Res. 2019; 38(1):117-127. PMC: 6917960. DOI: 10.1002/jor.24406. View

13.

Chern Y, Wong J, Cheng G, Yu A, Yin Y, Schaeffer D . The interaction between SPARC and GRP78 interferes with ER stress signaling and potentiates apoptosis via PERK/eIF2α and IRE1α/XBP-1 in colorectal cancer. Cell Death Dis. 2019; 10(7):504. PMC: 6594974. DOI: 10.1038/s41419-019-1687-x. View

14.

Zhu Z, Zhang Y, Zhang Y, Zhang H, Liu W, Zhang N . Exosomes derived from human umbilical cord mesenchymal stem cells accelerate growth of VK2 vaginal epithelial cells through MicroRNAs in vitro. Hum Reprod. 2018; 34(2):248-260. DOI: 10.1093/humrep/dey344. View

15.

Yao Z, Wang W, Ning J, Zhang X, Zheng W, Qian Y . Hydroxycamptothecin Inhibits Peritendinous Adhesion the Endoplasmic Reticulum Stress-Dependent Apoptosis. Front Pharmacol. 2019; 10:967. PMC: 6737834. DOI: 10.3389/fphar.2019.00967. View

16.

Lindholm D, Korhonen L, Eriksson O, Koks S . Recent Insights into the Role of Unfolded Protein Response in ER Stress in Health and Disease. Front Cell Dev Biol. 2017; 5:48. PMC: 5423914. DOI: 10.3389/fcell.2017.00048. View

17.

Sung D, Chang Y, Sung S, Ahn S, Park W . Thrombin Preconditioning of Extracellular Vesicles Derived from Mesenchymal Stem Cells Accelerates Cutaneous Wound Healing by Boosting Their Biogenesis and Enriching Cargo Content. J Clin Med. 2019; 8(4). PMC: 6517934. DOI: 10.3390/jcm8040533. View

18.

Meldolesi J . Exosomes and Ectosomes in Intercellular Communication. Curr Biol. 2018; 28(8):R435-R444. DOI: 10.1016/j.cub.2018.01.059. View

19.

Ackerman J, Nichols A, Studentsova V, Best K, Knapp E, Loiselle A . Cell non-autonomous functions of S100a4 drive fibrotic tendon healing. Elife. 2019; 8. PMC: 6546390. DOI: 10.7554/eLife.45342. View

20.

Fang S, Xu C, Zhang Y, Xue C, Yang C, Bi H . Umbilical Cord-Derived Mesenchymal Stem Cell-Derived Exosomal MicroRNAs Suppress Myofibroblast Differentiation by Inhibiting the Transforming Growth Factor-β/SMAD2 Pathway During Wound Healing. Stem Cells Transl Med. 2016; 5(10):1425-1439. PMC: 5031180. DOI: 10.5966/sctm.2015-0367. View