Effect of pulsed electromagnetic fields on mesenchymal stem cell-derived exosomes in inhibiting chondrocyte apoptosis_Journal of Biomedical Engineering

Authors：

XU Yang ^1,2,3 , WANG Qian ^1,2,3 , WANG Xiangxiu ^1,3 , XIANG Xiaona ^1,2,3 , PENG Jialei ^1,2 , ZHANG Jiangyin ^1,2,3 ,  HE Hongchen ^1,2,3

1. Rehabilitation Medicine Centre, West China Hospital of Sichuan University, Chengdu 610041, P. R. China;
2. West China School of Medicine, Sichuan University, Chengdu 610041, P. R. China;
3. Rehabilitation Medicine Key Laboratory of Sichuan Province, West China Hospital of Sichuan University, Chengdu 610041, P. R. China;

Corresponding author：

HE Hongchen, Email: hxkfhhc@126.com

Keywords：

Pulsed electromagnetic fields; Mesenchymal stem cells; Exosomes; Apoptosis; Chondrocyte

DOI：

10.7507/1001-5515.202209053

Video：

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The study aims to explore the effect of mesenchymal stem cells-derived exosomes (MSCs-Exo) on staurosporine (STS)-induced chondrocyte apoptosis before and after exposure to pulsed electromagnetic field (PEMF) at different frequencies. The AMSCs were extracted from the epididymal fat of healthy rats before and after exposure to the PEMF at 1 mT amplitude and a frequency of 15, 45, and 75 Hz, respectively, in an incubator. MSCs-Exo was extracted and identified. Exosomes were labeled with DiO fluorescent dye, and then co-cultured with STS-induced chondrocytes for 24 h. Cellular uptake of MSC-Exo, apoptosis, and the protein and mRNA expression of aggrecan, caspase-3 and collagenⅡA in chondrocytes were observed. The study demonstrated that the exposure of 75 Hz PEMF was superior to 15 and 45 Hz PEMF in enhancing the effect of exosomes in alleviating chondrocyte apoptosis and promoting cell matrix synthesis. This study lays a foundation for the regulatory mechanism of PEMF stimulation on MSCs-Exo in inhibiting chondrocyte apoptosis, and opens up a new direction for the prevention and treatment of osteoarthritis.

Citation： XU Yang, WANG Qian, WANG Xiangxiu, XIANG Xiaona, PENG Jialei, ZHANG Jiangyin, HE Hongchen. Effect of pulsed electromagnetic fields on mesenchymal stem cell-derived exosomes in inhibiting chondrocyte apoptosis. Journal of Biomedical Engineering, 2023, 40(1): 95-102. doi: 10.7507/1001-5515.202209053 Copy

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2.	Roseti L, Desando G, Cavallo C, et al. Articular cartilage regeneration in osteoarthritis. Cells, 2019, 8(11): 1305.
3.	Buckwalter J A, Mankin H J. Articular cartilage: degeneration and osteoarthritis, repair, regeneration, and transplantation. Instr Course Lect, 1998, 47: 487-504.
4.	Varela-Eirin M, Louriro J, Fonseca E, et al. Cartilage regeneration and ageing: targeting cellular plasticity in osteoarthritis. Ageing Res Rev, 2018, 42: 56-71.
5.	Hwang H S, Kim H A. Chondrocyte apoptosis in the pathogenesis of osteoarthritis. Int J Mol Sci, 2015, 16(11): 26035-26054.
6.	Abramoff B, Caldrea F E. Osteoarthritis: pathology, diagnosis, and treatment options. Med Clin North Am, 2020, 104(2): 293-311.
7.	Makris E A, Gomoll A H, Malizos K N, et al. Repair and tissue engineering techniques for articular cartilage. Nat Rev Rheumatol, 2015, 11(1): 21-34.
8.	Ding N, Li E, Ouyang X, et al. The therapeutic potential of bone marrow mesenchymal stem cells for articular cartilage regeneration in osteoarthritis. Curr Stem Cell Res Ther, 2021, 16(7): 840-857.
9.	Taghiyar L, Jahangir S, Khozaei R M, et al. Cartilage repair by mesenchymal stem cell-derived exosomes: preclinical and clinical trial update and perspectives. Adv Exp Med Biol, 2021, 1326: 73-93.
10.	Fuloria S, Subramaniyan V, Dahiya R, et al. Mesenchymal stem cell-derived extracellular vesicles: regenerative potential and challenges. Biology, 2021, 10(3): 172.
11.	Chang Y H, Wu K C, Liu H W, et al. Human umbilical cord-derived mesenchymal stem cells reduce monosodium iodoacetate-induced apoptosis in cartilage. Ci Ji Yi Xue Za Zhi, 2018, 30(2): 71-80.
12.	Daish C, Blanchard R, Fox K, et al. The application of pulsed electromagnetic fields (PEMFs) for bone fracture repair: past and perspective findings. Ann Biomed Eng, 2018, 46(4): 525-542.
13.	Zhu S, He H, Zhang C, et al. Effects of pulsed electromagnetic fields on postmenopausal osteoporosis. Bioelectromagnetics, 2017, 38(6): 406-424.
14.	Yang X, He H, Ye W, et al. Effects of pulsed electromagnetic field therapy on pain, stiffness, physical function, and quality of life in patients with osteoarthritis: a systematic review and meta-analysis of randomized placebo-controlled trials. Phys Ther, 2020, 100(7): 1118-1131.
15.	Ye W, Guo H, Yang X, et al. Pulsed electromagnetic field versus whole body vibration on cartilage and subchondral trabecular bone in mice with knee osteoarthritis. Bioelectromagnetics, 2020, 41(4): 298-307.
16.	Yang X, He H, Gao Q, et al. Pulsed electromagnetic field improves subchondral bone microstructure in knee osteoarthritis rats through a Wnt/β-catenin signaling-associated mechanism. Bioelectromagnetics, 2018, 39(2): 89-97.
17.	Yang X, He H, Zhou Y, et al. Pulsed electromagnetic field at different stages of knee osteoarthritis in rats induced by low-dose monosodium iodoacetate: effect on subchondral trabecular bone microarchitecture and cartilage degradation. Bioelectromagnetics, 2017, 38(3): 227-238.
18.	Parate D, Kadir N D, Celik C, et al. Pulsed electromagnetic fields potentiate the paracrine function of mesenchymal stem cells for cartilage regeneration. Stem Cell Res Ther, 2020, 11(1): 46.
19.	Yang X, Guo H, Ye W, et al. Pulsed electromagnetic field attenuates osteoarthritis progression in a murine destabilization-induced model through inhibition of TNF-α and IL-6 signaling. Cartilage, 2021, 13(2_suppl): 1665S-1675S.
20.	Barnett R. Osteoarthritis. Lancet, 2018, 391(10134): 1985.
21.	Xia B, Di C, Zhang J, et al. Osteoarthritis pathogenesis: a review of molecular mechanisms. Calcif Tissue Int, 2014, 95(6): 495-505.
22.	Castrogiovanni P, Ravalli S, Musumeci G. Apoptosis and autophagy in the pathogenesis of osteoarthritis. J Invest Surg, 2020, 33(9): 874-885.
23.	Uder C, Brückner S, Winkler S, et al. Mammalian MSC from selected species: features and applications. Cytometry A, 2018, 93(1): 32-49.
24.	Song Y, Du H, Dai C, et al. Human adipose-derived mesenchymal stem cells for osteoarthritis: a pilot study with long-term follow-up and repeated injections. Regen Med, 2018, 13(3): 295-307.
25.	Han S B, Seo I W, Shin Y S. Intra-articular injections of hyaluronic acid or steroids associated with better outcomes than platelet-rich plasma, adipose mesenchymal stromal cells, or placebo in knee osteoarthritis: a network meta-analysis. Arthroscopy, 2021, 37(1): 292-306.
26.	Mancuso P, Raman S, Glynn A, et al. Mesenchymal stem cell therapy for osteoarthritis: the critical role of the cell secretome. Front Bioeng Biotechnol, 2019, 7: 9.
27.	Phinney D G, Pittenger M F. Concise review: MSC-derived exosomes for cell-free therapy. Stem cells, 2017, 35(4): 851-868.
28.	Toh W S, Lai R C, Zhang B, et al. MSC exosome works through a protein-based mechanism of action. Biochem Soc Trans, 2018, 46(4): 843-853.
29.	Wechsler M E, Rao V V, Borelli A N, et al. Engineering the MSC secretome: a hydrogel focused approach. Adv Healthc Mater, 2021, 10(7): e2001948.
30.	Feng K, Xie X, Yuan J, et al. Reversing the surface charge of MSC-derived small extracellular vesicles by εPL-PEG-DSPE for enhanced osteoarthritis treatment. J Extracell Vesicles, 2021, 10(13): e12160.
31.	Ross C L, Ang D C, Almeida-Porada G. Targeting mesenchymal stromal cells/pericytes (MSCs) with pulsed electromagnetic field (PEMF) has the potential to treat rheumatoid arthritis. Front Immunol, 2019, 10: 266.
32.	Gaynor J S, Hagberg S, Gurfein B T. Veterinary applications of pulsed electromagnetic field therapy. Res Vet Sci, 2018, 119: 1-8.
33.	Androjna C, Yee C S, White C R, et al. A comparison of alendronate to varying magnitude PEMF in mitigating bone loss and altering bone remodeling in skeletally mature osteoporotic rats. Bone, 2021, 143: 115761.
34.	Vadalà M, Morales-Medina J C, Vallelunga A, et al. Mechanisms and therapeutic effectiveness of pulsed electromagnetic field therapy in oncology. Cancer Med, 2016, 5(11): 3128-3139.
35.	Ongaro A, Varani K, Masieri F F, et al. Electromagnetic fields (EMFs) and adenosine receptors modulate prostaglandin E(2) and cytokine release in human osteoarthritic synovial fibroblasts. J Cell Physiol, 2012, 227(6): 2461-2479.
36.	Fitzsimmons R J, Gordon S L, Kronberg J, et al. A pulsing electric field (PEF) increases human chondrocyte proliferation through a transduction pathway involving nitric oxide signaling. J Orthop Res, 2008, 26(6): 854-869.
37.	Stolberg-Stolberg J, Boettcher A, Sambale M, et al. Toll-like receptor 3 activation promotes joint degeneration in osteoarthritis. Cell Death Dis, 2022, 13(3): 224.
38.	Belmokhtar C A, Hillion J, Ségal-Bendirdjian E. Staurosporine induces apoptosis through both caspase-dependent and caspase-independent mechanisms. Oncogene, 2001, 20(26): 3354-3362.
39.	Bridgewater L C, Lefebvre V, de Crombrugghe B. Chondrocyte-specific enhancer elements in the Col11a2 gene resemble the Col2a1 tissue-specific enhancer. J Biol Chem, 1998, 273(24): 14998-15006.
40.	Kiani C, Chen L, Wu Y J, et al. Structure and function of aggrecan. Cell Res, 2002, 12(1): 19-32.
41.	Lian C, Wang X, Qiu X, et al. Collagen type II suppresses articular chondrocyte hypertrophy and osteoarthritis progression by promoting integrin β1-SMAD1 interaction. Bone Res, 2019, 7: 8.
42.	Sun K, Luo J, Guo J, et al. The PI3K/AKT/mTOR signaling pathway in osteoarthritis: a narrative review. Osteoarthritis Cartilage, 2020, 28(4): 400-419.
43.	Bao J, Chen Z, Xu L, et al. Rapamycin protects chondrocytes against IL-18-induced apoptosis and ameliorates rat osteoarthritis. Aging, 2020, 12(6): 5152-5167.
44.	Zhang Y, Cai W, Han G, et al. Panax notoginseng saponins prevent senescence and inhibit apoptosis by regulating the PI3K-AKT-mTOR pathway in osteoarthritic chondrocytes. Int J Mol Med, 2020, 45(4): 1225-1236.
45.	Han G, Zhang Y, Li H. The combination treatment of curcumin and probucol protects chondrocytes from TNF-α induced inflammation by enhancing autophagy and reducing apoptosis via the PI3K-Akt-mTOR pathway. Oxid Med Cell Longev, 2021, 2021: 5558066.
46.	Sun L, Zheng W, Liu Q D, et al. Valproic acid protects chondrocytes from LPS-stimulated damage via regulating miR-302d-3p/ITGB4 axis and mediating the PI3K-AKT signaling pathway. Front Mol Biosci, 2021, 8: 633315.

1. Glyn-Jones S, Palmer A J, Agricola R, et al. Osteoarthritis. Lancet (London), 2015, 386(9991): 376-387.
2. Roseti L, Desando G, Cavallo C, et al. Articular cartilage regeneration in osteoarthritis. Cells, 2019, 8(11): 1305.
3. Buckwalter J A, Mankin H J. Articular cartilage: degeneration and osteoarthritis, repair, regeneration, and transplantation. Instr Course Lect, 1998, 47: 487-504.
4. Varela-Eirin M, Louriro J, Fonseca E, et al. Cartilage regeneration and ageing: targeting cellular plasticity in osteoarthritis. Ageing Res Rev, 2018, 42: 56-71.
5. Hwang H S, Kim H A. Chondrocyte apoptosis in the pathogenesis of osteoarthritis. Int J Mol Sci, 2015, 16(11): 26035-26054.
6. Abramoff B, Caldrea F E. Osteoarthritis: pathology, diagnosis, and treatment options. Med Clin North Am, 2020, 104(2): 293-311.
7. Makris E A, Gomoll A H, Malizos K N, et al. Repair and tissue engineering techniques for articular cartilage. Nat Rev Rheumatol, 2015, 11(1): 21-34.
8. Ding N, Li E, Ouyang X, et al. The therapeutic potential of bone marrow mesenchymal stem cells for articular cartilage regeneration in osteoarthritis. Curr Stem Cell Res Ther, 2021, 16(7): 840-857.
9. Taghiyar L, Jahangir S, Khozaei R M, et al. Cartilage repair by mesenchymal stem cell-derived exosomes: preclinical and clinical trial update and perspectives. Adv Exp Med Biol, 2021, 1326: 73-93.
10. Fuloria S, Subramaniyan V, Dahiya R, et al. Mesenchymal stem cell-derived extracellular vesicles: regenerative potential and challenges. Biology, 2021, 10(3): 172.
11. Chang Y H, Wu K C, Liu H W, et al. Human umbilical cord-derived mesenchymal stem cells reduce monosodium iodoacetate-induced apoptosis in cartilage. Ci Ji Yi Xue Za Zhi, 2018, 30(2): 71-80.
12. Daish C, Blanchard R, Fox K, et al. The application of pulsed electromagnetic fields (PEMFs) for bone fracture repair: past and perspective findings. Ann Biomed Eng, 2018, 46(4): 525-542.
13. Zhu S, He H, Zhang C, et al. Effects of pulsed electromagnetic fields on postmenopausal osteoporosis. Bioelectromagnetics, 2017, 38(6): 406-424.
14. Yang X, He H, Ye W, et al. Effects of pulsed electromagnetic field therapy on pain, stiffness, physical function, and quality of life in patients with osteoarthritis: a systematic review and meta-analysis of randomized placebo-controlled trials. Phys Ther, 2020, 100(7): 1118-1131.
15. Ye W, Guo H, Yang X, et al. Pulsed electromagnetic field versus whole body vibration on cartilage and subchondral trabecular bone in mice with knee osteoarthritis. Bioelectromagnetics, 2020, 41(4): 298-307.
16. Yang X, He H, Gao Q, et al. Pulsed electromagnetic field improves subchondral bone microstructure in knee osteoarthritis rats through a Wnt/β-catenin signaling-associated mechanism. Bioelectromagnetics, 2018, 39(2): 89-97.
17. Yang X, He H, Zhou Y, et al. Pulsed electromagnetic field at different stages of knee osteoarthritis in rats induced by low-dose monosodium iodoacetate: effect on subchondral trabecular bone microarchitecture and cartilage degradation. Bioelectromagnetics, 2017, 38(3): 227-238.
18. Parate D, Kadir N D, Celik C, et al. Pulsed electromagnetic fields potentiate the paracrine function of mesenchymal stem cells for cartilage regeneration. Stem Cell Res Ther, 2020, 11(1): 46.
19. Yang X, Guo H, Ye W, et al. Pulsed electromagnetic field attenuates osteoarthritis progression in a murine destabilization-induced model through inhibition of TNF-α and IL-6 signaling. Cartilage, 2021, 13(2_suppl): 1665S-1675S.
20. Barnett R. Osteoarthritis. Lancet, 2018, 391(10134): 1985.
21. Xia B, Di C, Zhang J, et al. Osteoarthritis pathogenesis: a review of molecular mechanisms. Calcif Tissue Int, 2014, 95(6): 495-505.
22. Castrogiovanni P, Ravalli S, Musumeci G. Apoptosis and autophagy in the pathogenesis of osteoarthritis. J Invest Surg, 2020, 33(9): 874-885.
23. Uder C, Brückner S, Winkler S, et al. Mammalian MSC from selected species: features and applications. Cytometry A, 2018, 93(1): 32-49.
24. Song Y, Du H, Dai C, et al. Human adipose-derived mesenchymal stem cells for osteoarthritis: a pilot study with long-term follow-up and repeated injections. Regen Med, 2018, 13(3): 295-307.
25. Han S B, Seo I W, Shin Y S. Intra-articular injections of hyaluronic acid or steroids associated with better outcomes than platelet-rich plasma, adipose mesenchymal stromal cells, or placebo in knee osteoarthritis: a network meta-analysis. Arthroscopy, 2021, 37(1): 292-306.
26. Mancuso P, Raman S, Glynn A, et al. Mesenchymal stem cell therapy for osteoarthritis: the critical role of the cell secretome. Front Bioeng Biotechnol, 2019, 7: 9.
27. Phinney D G, Pittenger M F. Concise review: MSC-derived exosomes for cell-free therapy. Stem cells, 2017, 35(4): 851-868.
28. Toh W S, Lai R C, Zhang B, et al. MSC exosome works through a protein-based mechanism of action. Biochem Soc Trans, 2018, 46(4): 843-853.
29. Wechsler M E, Rao V V, Borelli A N, et al. Engineering the MSC secretome: a hydrogel focused approach. Adv Healthc Mater, 2021, 10(7): e2001948.
30. Feng K, Xie X, Yuan J, et al. Reversing the surface charge of MSC-derived small extracellular vesicles by εPL-PEG-DSPE for enhanced osteoarthritis treatment. J Extracell Vesicles, 2021, 10(13): e12160.
31. Ross C L, Ang D C, Almeida-Porada G. Targeting mesenchymal stromal cells/pericytes (MSCs) with pulsed electromagnetic field (PEMF) has the potential to treat rheumatoid arthritis. Front Immunol, 2019, 10: 266.
32. Gaynor J S, Hagberg S, Gurfein B T. Veterinary applications of pulsed electromagnetic field therapy. Res Vet Sci, 2018, 119: 1-8.
33. Androjna C, Yee C S, White C R, et al. A comparison of alendronate to varying magnitude PEMF in mitigating bone loss and altering bone remodeling in skeletally mature osteoporotic rats. Bone, 2021, 143: 115761.
34. Vadalà M, Morales-Medina J C, Vallelunga A, et al. Mechanisms and therapeutic effectiveness of pulsed electromagnetic field therapy in oncology. Cancer Med, 2016, 5(11): 3128-3139.
35. Ongaro A, Varani K, Masieri F F, et al. Electromagnetic fields (EMFs) and adenosine receptors modulate prostaglandin E(2) and cytokine release in human osteoarthritic synovial fibroblasts. J Cell Physiol, 2012, 227(6): 2461-2479.
36. Fitzsimmons R J, Gordon S L, Kronberg J, et al. A pulsing electric field (PEF) increases human chondrocyte proliferation through a transduction pathway involving nitric oxide signaling. J Orthop Res, 2008, 26(6): 854-869.
37. Stolberg-Stolberg J, Boettcher A, Sambale M, et al. Toll-like receptor 3 activation promotes joint degeneration in osteoarthritis. Cell Death Dis, 2022, 13(3): 224.
38. Belmokhtar C A, Hillion J, Ségal-Bendirdjian E. Staurosporine induces apoptosis through both caspase-dependent and caspase-independent mechanisms. Oncogene, 2001, 20(26): 3354-3362.
39. Bridgewater L C, Lefebvre V, de Crombrugghe B. Chondrocyte-specific enhancer elements in the Col11a2 gene resemble the Col2a1 tissue-specific enhancer. J Biol Chem, 1998, 273(24): 14998-15006.
40. Kiani C, Chen L, Wu Y J, et al. Structure and function of aggrecan. Cell Res, 2002, 12(1): 19-32.
41. Lian C, Wang X, Qiu X, et al. Collagen type II suppresses articular chondrocyte hypertrophy and osteoarthritis progression by promoting integrin β1-SMAD1 interaction. Bone Res, 2019, 7: 8.
42. Sun K, Luo J, Guo J, et al. The PI3K/AKT/mTOR signaling pathway in osteoarthritis: a narrative review. Osteoarthritis Cartilage, 2020, 28(4): 400-419.
43. Bao J, Chen Z, Xu L, et al. Rapamycin protects chondrocytes against IL-18-induced apoptosis and ameliorates rat osteoarthritis. Aging, 2020, 12(6): 5152-5167.
44. Zhang Y, Cai W, Han G, et al. Panax notoginseng saponins prevent senescence and inhibit apoptosis by regulating the PI3K-AKT-mTOR pathway in osteoarthritic chondrocytes. Int J Mol Med, 2020, 45(4): 1225-1236.
45. Han G, Zhang Y, Li H. The combination treatment of curcumin and probucol protects chondrocytes from TNF-α induced inflammation by enhancing autophagy and reducing apoptosis via the PI3K-Akt-mTOR pathway. Oxid Med Cell Longev, 2021, 2021: 5558066.
46. Sun L, Zheng W, Liu Q D, et al. Valproic acid protects chondrocytes from LPS-stimulated damage via regulating miR-302d-3p/ITGB4 axis and mediating the PI3K-AKT signaling pathway. Front Mol Biosci, 2021, 8: 633315.

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