Low-Intensity Pulsed Ultrasound Enhances the Efficacy of Bone Marrow-Derived MSCs in Osteoarthritis Cartilage Repair by Regulating Autophagy-Mediated Exosome Release

Overview

Journal Cartilage

Date 2022 Apr 19

PMID 35438034

Authors

Peng Xia

Qi Wang

Jiulong Song

Xiaoju Wang

Xinwei Wang

Qiang Lin

Kai Cheng

Anliang Chen

Xueping Li

Affiliations

Soon will be listed here.

Abstract

Objective: The present study explored whether low-intensity pulsed ultrasound (LIPUS) enhances the therapeutic efficacy of mesenchymal stem cells (MSCs) in osteoarthritis (OA) cartilage repair by regulating autophagy-mediated exosome release.

Design: MSCs were isolated from the rat bone marrow and treated with rapamycin, 3-methyladenine, or LIPUS. The mechanism of the LIPUS-stimulated exosome release by MSCs was analyzed by inhibiting autophagy. In addition, the MSCs were co-cultured with OA chondrocytes and stimulated by LIPUS, with or without exosome release inhibitor intervention. The exosome release was detected through transmission electron microscopy (TEM), nanoparticle tracking analysis, and biomarker expression analysis. Autophagy was analyzed through TEM, autophagy-related gene expression analysis, and immunofluorescence analysis . Furthermore, a rat knee OA model was constructed and treated with MSCs, GW4869, and LIPUS. The cartilage repair was assessed through histopathological analysis and extracellular matrix protein expression analysis.

Results: The results indicated that LIPUS promoted MSC exosome release by activating autophagy. The results demonstrated that LIPUS significantly enhanced the positive effects of MSCs on OA cartilage. These effects were significantly blocked by GW4869, an inhibitor of exosome release.

Conclusions: LIPUS can enhance the therapeutic efficacy of MSCs in OA cartilage repair, and the underlying mechanism is related to the increase in autophagy-mediated exosome release.

Citing Articles

Evaluation of efficacy and safety of low-intensity pulsed ultrasound in patients with concurrent erectile dysfunction and chronic prostatitis/chronic pelvic pain syndrome: a prospective, randomized controlled study.

Li Z, Li D, Zu X, Xiang B, Wang G, Tang Z BMC Urol. 2024; 24(1):232.

PMID: 39438979 PMC: 11495096. DOI: 10.1186/s12894-024-01630-5.

Mesenchymal stem cell-derived extracellular vesicles in joint diseases: Therapeutic effects and underlying mechanisms.

Wu J, Wu J, Liu Z, Gong Y, Feng D, Xiang W J Orthop Translat. 2024; 48:53-69.

PMID: 39170747 PMC: 11338158. DOI: 10.1016/j.jot.2024.07.005.

Acoustic vibration promotes in vitro expansion of human embryonic stem cells.

Hu X, Duan H, Zou D, Dong C, Wang Y, Wang Y Am J Stem Cells. 2024; 13(3):143-151.

PMID: 39021373 PMC: 11249672. DOI: 10.62347/PJFC2708.

Mesenchymal stem cell-derived extracellular vesicles: a regulator and carrier for targeting bone-related diseases.

Tang J, Wang X, Lin X, Wu C Cell Death Discov. 2024; 10(1):212.

PMID: 38697996 PMC: 11066013. DOI: 10.1038/s41420-024-01973-w.

Effectiveness of low-intensity pulsed ultrasound on osteoarthritis: molecular mechanism and tissue engineering.

Zhou J, Ning E, Lu L, Zhang H, Yang X, Hao Y Front Med (Lausanne). 2024; 11:1292473.

PMID: 38695024 PMC: 11061361. DOI: 10.3389/fmed.2024.1292473.

References

Zhang X, He S, Liang X, Li W, Li T, Li D . Aging, Cell Senescence, the Pathogenesis and Targeted Therapies of Osteoarthritis. Front Pharmacol. 2021; 12:728100. PMC: 8419276. DOI: 10.3389/fphar.2021.728100. View

Xing H, Tan J, Miao Y, Lv Y, Zhang Q . Crosstalk between exosomes and autophagy: A review of molecular mechanisms and therapies. J Cell Mol Med. 2021; 25(5):2297-2308. PMC: 7933923. DOI: 10.1111/jcmm.16276. View

Zhu C, Wu W, Qu X . Mesenchymal stem cells in osteoarthritis therapy: a review. Am J Transl Res. 2021; 13(2):448-461. PMC: 7868850. View

Wang Y, Yuan M, Guo Q, Lu S, Peng J . Mesenchymal Stem Cells for Treating Articular Cartilage Defects and Osteoarthritis. Cell Transplant. 2014; 24(9):1661-78. DOI: 10.3727/096368914X683485. View

Kusuyama J, Bandow K, Shamoto M, Kakimoto K, Ohnishi T, Matsuguchi T . Low intensity pulsed ultrasound (LIPUS) influences the multilineage differentiation of mesenchymal stem and progenitor cell lines through ROCK-Cot/Tpl2-MEK-ERK signaling pathway. J Biol Chem. 2014; 289(15):10330-10344. PMC: 4036157. DOI: 10.1074/jbc.M113.546382. View

Wang Y, Yu D, Liu Z, Zhou F, Dai J, Wu B . Exosomes from embryonic mesenchymal stem cells alleviate osteoarthritis through balancing synthesis and degradation of cartilage extracellular matrix. Stem Cell Res Ther. 2017; 8(1):189. PMC: 5556343. DOI: 10.1186/s13287-017-0632-0. View

Camussi G, Deregibus M, Bruno S, Cantaluppi V, Biancone L . Exosomes/microvesicles as a mechanism of cell-to-cell communication. Kidney Int. 2010; 78(9):838-48. DOI: 10.1038/ki.2010.278. View

Saxton R, Sabatini D . mTOR Signaling in Growth, Metabolism, and Disease. Cell. 2017; 168(6):960-976. PMC: 5394987. DOI: 10.1016/j.cell.2017.02.004. View

Schminke B, Miosge N . Cartilage repair in vivo: the role of migratory progenitor cells. Curr Rheumatol Rep. 2014; 16(11):461. PMC: 4169867. DOI: 10.1007/s11926-014-0461-4. View

10.

Dowthwaite G, Bishop J, Redman S, Khan I, Rooney P, Evans D . The surface of articular cartilage contains a progenitor cell population. J Cell Sci. 2004; 117(Pt 6):889-97. DOI: 10.1242/jcs.00912. View

11.

Xia P, Shen S, Lin Q, Cheng K, Ren S, Gao M . Low-Intensity Pulsed Ultrasound Treatment at an Early Osteoarthritis Stage Protects Rabbit Cartilage From Damage via the Integrin/Focal Adhesion Kinase/Mitogen-Activated Protein Kinase Signaling Pathway. J Ultrasound Med. 2015; 34(11):1991-9. DOI: 10.7863/ultra.14.10016. View

12.

Higashi H, Barendregt J . Cost-effectiveness of total hip and knee replacements for the Australian population with osteoarthritis: discrete-event simulation model. PLoS One. 2011; 6(9):e25403. PMC: 3179521. DOI: 10.1371/journal.pone.0025403. View

13.

Xia P, Ren S, Lin Q, Cheng K, Shen S, Gao M . Low-Intensity Pulsed Ultrasound Affects Chondrocyte Extracellular Matrix Production via an Integrin-Mediated p38 MAPK Signaling Pathway. Ultrasound Med Biol. 2015; 41(6):1690-700. DOI: 10.1016/j.ultrasmedbio.2015.01.014. View

14.

Toh W, Lai R, Hui J, Lim S . MSC exosome as a cell-free MSC therapy for cartilage regeneration: Implications for osteoarthritis treatment. Semin Cell Dev Biol. 2016; 67:56-64. DOI: 10.1016/j.semcdb.2016.11.008. View

15.

Hunter D, Bierma-Zeinstra S . Osteoarthritis. Lancet. 2019; 393(10182):1745-1759. DOI: 10.1016/S0140-6736(19)30417-9. View

16.

Lamo-Espinosa J, Mora G, Blanco J, Granero-Molto F, Nunez-Cordoba J, Lopez-Elio S . Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: long-term follow up of a multicenter randomized controlled clinical trial (phase I/II). J Transl Med. 2018; 16(1):213. PMC: 6069715. DOI: 10.1186/s12967-018-1591-7. View

17.

Zhang Q, Xiang E, Rao W, Zhang Y, Xiao C, Li C . Intra-articular injection of human umbilical cord mesenchymal stem cells ameliorates monosodium iodoacetate-induced osteoarthritis in rats by inhibiting cartilage degradation and inflammation. Bone Joint Res. 2021; 10(3):226-236. PMC: 7998343. DOI: 10.1302/2046-3758.103.BJR-2020-0206.R2. View

18.

Tang Y, Zhou Y, Li H . Advances in mesenchymal stem cell exosomes: a review. Stem Cell Res Ther. 2021; 12(1):71. PMC: 7814175. DOI: 10.1186/s13287-021-02138-7. View

19.

da Silva Meirelles L, Maria Fontes A, Covas D, Caplan A . Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine Growth Factor Rev. 2009; 20(5-6):419-27. DOI: 10.1016/j.cytogfr.2009.10.002. View

20.

Johnstone R, Adam M, Hammond J, Orr L, Turbide C . Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Biol Chem. 1987; 262(19):9412-20. View