Mesenchymal stem cell–derived extracellular vesicles: a possible therapeutic strategy for orthopaedic diseases: a narrative review

doi:10.12336/biomatertransl.2022.03.002

Biomaterials Translational ›› 2022, Vol. 3 ›› Issue (3): 175-187.doi: 10.12336/biomatertransl.2022.03.002

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Mesenchymal stem cell–derived extracellular vesicles: a possible therapeutic strategy for orthopaedic diseases: a narrative review

Zhao–Lin Zeng²^,³, Hui Xie¹^,^*()

1 Department of Orthopaedics, Movement System Injury and Repair Research Centre, Xiangya Hospital, Central South University, Changsha, Hunan Province, China
2 Department of Metabolism and Endocrinology, The First Affliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan Province, China
3 Department of Clinical Medicine, The First Affliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan Province, China

Received:2022-04-28 Revised:2022-05-19 Accepted:2022-08-02 Online:2022-09-28 Published:2022-09-28
Contact: Hui Xie E-mail:huixie@csu.edu.cn
About author:Hui Xie, huixie@csu.edu.cn.

Abstract

Abstract:

Accumulating evidence suggests that the therapeutic role of mesenchymal stem cells (MSCs) in bone diseases is closely related to paracrine–generated extracellular vesicles (EVs). MSC–derived EVs (MSC–EVs) carry proteins, nucleic acids, and lipids to the extracellular space and affect the bone microenvironment. They have similar biological functions to MSCs, such as the ability to repair organ and tissue damage. In addition, MSC–EVs also have the advantages of long half–life, low immunogenicity, attractive stability, ability to pass through the blood–brain barrier, and demonstrate excellent performance with potential practical applications in bone diseases. In this review, we summarise the current applications and mechanisms of MSC–EVs in osteoporosis, osteoarthritis, bone tumours, osteonecrosis of the femoral head, and fractures, as well as the development of MSC–EVs combined with materials science in the field of orthopaedics. Additionally, we explore the critical challenges involved in the clinical application of MSC–EVs in orthopaedic diseases.

Key words: exosomes, extracellular vesicles, mesenchymal stem cells, orthopaedic diseases, regenerative medicine

1.	Han, Y.; You, X.; Xing, W.; Zhang, Z.; Zou, W. Paracrine and endocrine actions of bone-the functions of secretory proteins from osteoblasts, osteocytes, and osteoclasts. Bone Res. 2018, 6, 16. doi: 10.1038/s41413-018-0019-6 URL
2.	Kasza, K.; Gurnani, P.; Hardie, K. R.; Cámara, M.; Alexander, C. Challenges and solutions in polymer drug delivery for bacterial biofilm treatment: a tissue-by-tissue account. Adv Drug Deliv Rev. 2021, 178, 113973. doi: 10.1016/j.addr.2021.113973 URL
3.	Yao, D.; Huang, L.; Ke, J.; Zhang, M.; Xiao, Q.; Zhu, X. Bone metabolism regulation: implications for the treatment of bone diseases. Biomed Pharmacother. 2020, 129, 110494. doi: 10.1016/j.biopha.2020.110494 URL
4.	Rachner, T. D.; Khosla, S.; Hofbauer, L. C. Osteoporosis: now and the future. Lancet. 2011, 377, 1276-1287. doi: 10.1016/S0140-6736(10)62349-5 URL
5.	Zhou, W.; Shi, Y.; Wang, H.; Yu, C.; Zhu, H.; Wu, A. Sinensetin reduces osteoarthritis pathology in the tert-butyl hydroperoxide-treated chondrocytes and the destabilization of the medial meniscus model mice via the AMPK/mTOR signaling pathway. Front Pharmacol. 2021, 12, 713491. doi: 10.3389/fphar.2021.713491 URL
6.	Ullah, I.; Subbarao, R. B.; Rho, G. J. Human mesenchymal stem cells - current trends and future prospective. Biosci Rep. 2015, 35, e00191.
7.	Uccelli, A.; Moretta, L.; Pistoia, V. Mesenchymal stem cells in health and disease. Nat Rev Immunol. 2008, 8, 726-736. doi: 10.1038/nri2395 URL
8.	Zhou, T.; Yuan, Z.; Weng, J.; Pei, D.; Du, X.; He, C.; Lai, P. Challenges and advances in clinical applications of mesenchymal stromal cells. J Hematol Oncol. 2021, 14, 24. doi: 10.1186/s13045-021-01037-x URL
9.	Murphy, M. B.; Moncivais, K.; Caplan, A. I. Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine. Exp Mol Med. 2013, 45, e54.
10.	Ankrum, J. A.; Ong, J. F.; Karp, J. M. Mesenchymal stem cells: immune evasive, not immune privileged. Nat Biotechnol. 2014, 32, 252-260. doi: 10.1038/nbt.2816 URL
11.	Triffitt, J. T.; Wang, Q. Stem cell fate and microenvironment. Biomater Transl. 2022, 3, 1-2.
12.	Zeng, Z. L.; Yuan, Q.; Zu, X.; Liu, J. Insights into the role of mitochondria in vascular calcification. Front Cardiovasc Med. 2022, 9, 879752. doi: 10.3389/fcvm.2022.879752 URL
13.	Yáñez-Mó, M.; Siljander, P. R.; Andreu, Z.; Zavec, A. B.; Borràs, F. E.; Buzas, E. I.; Buzas, K.; Casal, E.; Cappello, F.; Carvalho, J.; Colás, E.; Cordeiro-da Silva, A.; Fais, S.; Falcon-Perez, J. M.; Ghobrial, I. M.; Giebel, B.; Gimona, M.; Graner, M.; Gursel, I.; Gursel, M.; Heegaard, N. H.; Hendrix, A.; Kierulf, P.; Kokubun, K.; Kosanovic, M.; Kralj-Iglic, V.; Krämer-Albers, E. M.; Laitinen, S.; Lässer, C.; Lener, T.; Ligeti, E.; Linē, A.; Lipps, G.; Llorente, A.; Lötvall, J.; Manček-Keber, M.; Marcilla, A.; Mittelbrunn, M.; Nazarenko, I.; Nolte-’t Hoen, E. N.; Nyman, T. A.; O’Driscoll, L.; Olivan, M.; Oliveira, C.; Pállinger, É.; Del Portillo, H. A.; Reventós, J.; Rigau, M.; Rohde, E.; Sammar, M.; Sánchez-Madrid, F.; Santarém, N.; Schallmoser, K.; Ostenfeld, M. S.; Stoorvogel, W.; Stukelj, R.; Van der Grein, S. G.; Vasconcelos, M. H.; Wauben, M. H.; De Wever, O. Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles. 2015, 4, 27066. doi: 10.3402/jev.v4.27066 URL
14.	Liu, S.; Xu, X.; Liang, S.; Chen, Z.; Zhang, Y.; Qian, A.; Hu, L. The application of MSCs-derived extracellular vesicles in bone disorders: novel cell-free therapeutic strategy. Front Cell Dev Biol. 2020, 8, 619. doi: 10.3389/fcell.2020.00619 URL
15.	Mousaei Ghasroldasht, M.; Seok, J.; Park, H. S.; Liakath Ali, F. B.; Al-Hendy, A. Stem cell therapy: from idea to clinical practice. Int J Mol Sci. 2022, 23, 2850. doi: 10.3390/ijms23052850 URL
16.	Nazari, H.; Zhang, L.; Zhu, D.; Chader, G. J.; Falabella, P.; Stefanini, F.; Rowland, T.; Clegg, D. O.; Kashani, A. H.; Hinton, D. R.; Humayun, M. S. Stem cell based therapies for age-related macular degeneration: the promises and the challenges. Prog Retin Eye Res. 2015, 48, 1-39. doi: 10.1016/j.preteyeres.2015.06.004 URL
17.	Ambrosi, T. H.; Longaker, M. T.; Chan, C. K. F. A revised perspective of skeletal stem cell biology. Front Cell Dev Biol. 2019, 7, 189. doi: 10.3389/fcell.2019.00189 URL
18.	Zeng, Z. L.; Lin, X. L.; Tan, L. L.; Liu, Y. M.; Qu, K.; Wang, Z. MicroRNAs: important regulators of induced pluripotent stem cell generation and differentiation. Stem Cell Rev Rep. 2018, 14, 71-81. doi: 10.1007/s12015-017-9785-6 URL
19.	Jin, J. Stem cell treatments. JAMA. 2017, 317, 330. doi: 10.1001/jama.2016.17822 URL
20.	Friedenstein, A. J.; Piatetzky, S., II; Petrakova, K. V. Osteogenesis in transplants of bone marrow cells. J Embryol Exp Morphol. 1966, 16, 381-390.
21.	Caplan, A. I. Mesenchymal stem cells. J Orthop Res. 1991, 9, 641-650. doi: 10.1002/jor.1100090504 URL
22.	Sacchetti, B.; Funari, A.; Michienzi, S.; Di Cesare, S.; Piersanti, S.; Saggio, I.; Tagliafico, E.; Ferrari, S.; Robey, P. G.; Riminucci, M.; Bianco, P. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell. 2007, 131, 324-336. doi: 10.1016/j.cell.2007.08.025 URL
23.	Lukomska, B.; Stanaszek, L.; Zuba-Surma, E.; Legosz, P.; Sarzynska, S.; Drela, K. Challenges and controversies in human mesenchymal stem cell therapy. Stem Cells Int. 2019, 2019, 9628536.
24.	Huang, Y.; Yang, L. Mesenchymal stem cells and extracellular vesicles in therapy against kidney diseases. Stem Cell Res Ther. 2021, 12, 219. doi: 10.1186/s13287-021-02289-7 URL
25.	Boulanger, C. M.; Loyer, X.; Rautou, P. E.; Amabile, N. Extracellular vesicles in coronary artery disease. Nat Rev Cardiol. 2017, 14, 259-272. doi: 10.1038/nrcardio.2017.7 URL
26.	Harding, C. V.; Heuser, J. E.; Stahl, P. D. Exosomes: looking back three decades and into the future. J Cell Biol. 2013, 200, 367-371. doi: 10.1083/jcb.201212113 URL
27.	Johnstone, R. M.; Adam, M.; Hammond, J. R.; Orr, L.; Turbide, C. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Biol Chem. 1987, 262, 9412-9420. doi: 10.1016/S0021-9258(18)48095-7 URL
28.	Théry, C.; Zitvogel, L.; Amigorena, S. Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002, 2, 569-579.
29.	Quiñones-Vico, M. I.; Sanabria-de la Torre, R.; Sánchez-Díaz, M.; Sierra-Sánchez, Á.; Montero-Vílchez, T.; Fernández-González, A.; Arias-Santiago, S. The role of exosomes derived from mesenchymal stromal cells in dermatology. Front Cell Dev Biol. 2021, 9, 647012. doi: 10.3389/fcell.2021.647012 URL
30.	Ruan, Z.; Pathak, D.; Venkatesan Kalavai, S.; Yoshii-Kitahara, A.; Muraoka, S.; Bhatt, N.; Takamatsu-Yukawa, K.; Hu, J.; Wang, Y.; Hersh, S.; Ericsson, M.; Gorantla, S.; Gendelman, H. E.; Kayed, R.; Ikezu, S.; Luebke, J. I.; Ikezu, T. Alzheimer’s disease brain-derived extracellular vesicles spread tau pathology in interneurons. Brain. 2021, 144, 288-309. doi: 10.1093/brain/awaa376 URL
31.	Maas, S. L. N.; Breakefield, X. O.; Weaver, A. M. Extracellular vesicles: unique intercellular delivery vehicles. Trends Cell Biol. 2017, 27, 172-188. doi: 10.1016/j.tcb.2016.11.003 URL
32.	Akers, J. C.; Gonda, D.; Kim, R.; Carter, B. S.; Chen, C. C. Biogenesis of extracellular vesicles (EV): exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies. J Neurooncol. 2013, 113, 1-11. doi: 10.1007/s11060-013-1084-8 URL
33.	Chotiyarnwong, P.; McCloskey, E. V. Pathogenesis of glucocorticoid-induced osteoporosis and options for treatment. Nat Rev Endocrinol. 2020, 16, 437-447. doi: 10.1038/s41574-020-0341-0 URL
34.	Pittenger, M. F.; Mackay, A. M.; Beck, S. C.; Jaiswal, R. K.; Douglas, R.; Mosca, J. D.; Moorman, M. A.; Simonetti, D. W.; Craig, S.; Marshak, D. R. Multilineage potential of adult human mesenchymal stem cells. Science. 1999, 284, 143-147. doi: 10.1126/science.284.5411.143 URL
35.	Takayanagi, H. Osteoimmunology and the effects of the immune system on bone. Nat Rev Rheumatol. 2009, 5, 667-676. doi: 10.1038/nrrheum.2009.217 URL
36.	Feng, X.; Teitelbaum, S. L. Osteoclasts: new insights. Bone Res. 2013, 1, 11-26. doi: 10.4248/BR201301003 URL
37.	Al-Bari, A. A.; Al Mamun, A. Current advances in regulation of bone homeostasis. FASEB Bioadv. 2020, 2, 668-679. doi: 10.1096/fba.2020-00058 URL
38.	Wu, J.; Zhang, W.; Ran, Q.; Xiang, Y.; Zhong, J. F.; Li, S. C.; Li, Z. The differentiation balance of bone marrow mesenchymal stem cells is crucial to hematopoiesis. Stem Cells Int. 2018, 2018, 1540148.
39.	Chen, G.; Zhuo, Y.; Tao, B.; Liu, Q.; Shang, W.; Li, Y.; Wang, Y.; Li, Y.; Zhang, L.; Fang, Y.; Zhang, X.; Fang, Z.; Yu, Y. Moderate SMFs attenuate bone loss in mice by promoting directional osteogenic differentiation of BMSCs. Stem Cell Res Ther. 2020, 11, 487. doi: 10.1186/s13287-020-02004-y URL
40.	Du, G.; Cheng, X.; Zhang, Z.; Han, L.; Wu, K.; Li, Y.; Lin, X. TGF-beta induced key genes of osteogenic and adipogenic differentiation in human mesenchymal stem cells and miRNA-mRNA regulatory networks. Front Genet. 2021, 12, 759596. doi: 10.3389/fgene.2021.759596 URL
41.	Meyer, M. B.; Benkusky, N. A.; Sen, B.; Rubin, J.; Pike, J. W. Epigenetic plasticity drives adipogenic and osteogenic differentiation of marrow-derived mesenchymal stem cells. J Biol Chem. 2016, 291, 17829-17847. doi: 10.1074/jbc.M116.736538 URL
42.	Robert, A. W.; Marcon, B. H.; Dallagiovanna, B.; Shigunov, P. Adipogenesis, osteogenesis, and chondrogenesis of human mesenchymal stem/stromal cells: a comparative transcriptome approach. Front Cell Dev Biol. 2020, 8, 561. doi: 10.3389/fcell.2020.00561 URL
43.	Kolf, C. M.; Cho, E.; Tuan, R. S. Mesenchymal stromal cells. Biology of adult mesenchymal stem cells: regulation of niche, self-renewal and differentiation. Arthritis Res Ther. 2007, 9, 204. doi: 10.1186/ar2116 URL
44.	Yang, X.; Yang, J.; Lei, P.; Wen, T. LncRNA MALAT1 shuttled by bone marrow-derived mesenchymal stem cells-secreted exosomes alleviates osteoporosis through mediating microRNA-34c/SATB2 axis. Aging (Albany N Y). 2019, 11, 8777-8791.
45.	Qiu, M.; Zhai, S.; Fu, Q.; Liu, D. Bone marrow mesenchymal stem cells-derived exosomal microRNA-150-3p promotes osteoblast proliferation and differentiation in osteoporosis. Hum Gene Ther. 2021, 32, 717-729. doi: 10.1089/hum.2020.005 URL
46.	Huang, B.; Su, Y.; Shen, E.; Song, M.; Liu, D.; Qi, H. Extracellular vesicles from GPNMB-modified bone marrow mesenchymal stem cells attenuate bone loss in an ovariectomized rat model. Life Sci. 2021, 272, 119208. doi: 10.1016/j.lfs.2021.119208 URL
47.	Hu, Y.; Li, X.; Zhang, Q.; Gu, Z.; Luo, Y.; Guo, J.; Wang, X.; Jing, Y.; Chen, X.; Su, J. Exosome-guided bone targeted delivery of Antagomir-188 as an anabolic therapy for bone loss. Bioact Mater. 2021, 6, 2905-2913.
48.	Wang, X.; Li, X.; Li, J.; Zhai, L.; Liu, D.; Abdurahman, A.; Zhang, Y.; Yokota, H.; Zhang, P. Mechanical loading stimulates bone angiogenesis through enhancing type H vessel formation and downregulating exosomal miR-214-3p from bone marrow-derived mesenchymal stem cells. FASEB J. 2021, 35, e21150.
49.	Bond, J.; Adams, S.; Richards, S.; Vora, A.; Mitchell, C.; Goulden, N. Polymorphism in the PAI-1 (SERPINE1) gene and the risk of osteonecrosis in children with acute lymphoblastic leukemia. Blood. 2011, 118, 2632-2633.
50.	Li, L.; Wang, Y.; Yu, X.; Bao, Y.; An, L.; Wei, X.; Yu, W.; Liu, B.; Li, J.; Yang, J.; Xia, Y.; Liu, G.; Cao, F.; Zhang, X.; Zhao, D. Bone marrow mesenchymal stem cell-derived exosomes promote plasminogen activator inhibitor 1 expression in vascular cells in the local microenvironment during rabbit osteonecrosis of the femoral head. Stem Cell Res Ther. 2020, 11, 480. doi: 10.1186/s13287-020-01991-2 URL
51.	Liao, W.; Ning, Y.; Xu, H. J.; Zou, W. Z.; Hu, J.; Liu, X. Z.; Yang, Y.; Li, Z. H. BMSC-derived exosomes carrying microRNA-122-5p promote proliferation of osteoblasts in osteonecrosis of the femoral head. Clin Sci (Lond). 2019, 133, 1955-1975. doi: 10.1042/CS20181064 URL
52.	Kuang, M. J.; Huang, Y.; Zhao, X. G.; Zhang, R.; Ma, J. X.; Wang, D. C.; Ma, X. L. Exosomes derived from Wharton’s jelly of human umbilical cord mesenchymal stem cells reduce osteocyte apoptosis in glucocorticoid-induced osteonecrosis of the femoral head in rats via the miR-21-PTEN-AKT signalling pathway. Int J Biol Sci. 2019, 15, 1861-1871. doi: 10.7150/ijbs.32262 URL
53.	Tao, S. C.; Yuan, T.; Zhang, Y. L.; Yin, W. J.; Guo, S. C.; Zhang, C. Q. Exosomes derived from miR-140-5p-overexpressing human synovial mesenchymal stem cells enhance cartilage tissue regeneration and prevent osteoarthritis of the knee in a rat model. Theranostics. 2017, 7, 180-195. doi: 10.7150/thno.17133 URL
54.	Tofiño-Vian, M.; Guillén, M. I.; Pérez Del Caz, M. D.; Silvestre, A.; Alcaraz, M. J. Microvesicles from human adipose tissue-derived mesenchymal stem cells as a new protective strategy in osteoarthritic chondrocytes. Cell Physiol Biochem. 2018, 47, 11-25. doi: 10.1159/000489739 URL
55.	Wu, J.; Kuang, L.; Chen, C.; Yang, J.; Zeng, W. N.; Li, T.; Chen, H.; Huang, S.; Fu, Z.; Li, J.; Liu, R.; Ni, Z.; Chen, L.; Yang, L. miR-100-5p-abundant exosomes derived from infrapatellar fat pad MSCs protect articular cartilage and ameliorate gait abnormalities via inhibition of mTOR in osteoarthritis. Biomaterials. 2019, 206, 87-100. doi: 10.1016/j.biomaterials.2019.03.022 URL
56.	Wang, Y.; Chu, Y.; Li, K.; Zhang, G.; Guo, Z.; Wu, X.; Qiu, C.; Li, Y.; Wan, X.; Sui, J.; Zhang, D.; Xiang, H.; Chen, B. Exosomes secreted by adipose-derived mesenchymal stem cells foster metastasis and osteosarcoma proliferation by increasing COLGALT2 expression. Front Cell Dev Biol. 2020, 8, 353. doi: 10.3389/fcell.2020.00353 URL
57.	Vallabhaneni, K. C.; Hassler, M. Y.; Abraham, A.; Whitt, J.; Mo, Y. Y.; Atfi, A.; Pochampally, R. Mesenchymal stem/stromal cells under stress increase osteosarcoma migration and apoptosis resistance via extracellular vesicle mediated communication. PLoS One. 2016, 11, e0166027.
58.	Li, F.; Chen, X.; Shang, C.; Ying, Q.; Zhou, X.; Zhu, R.; Lu, H.; Hao, X.; Dong, Q.; Jiang, Z. Bone marrow mesenchymal stem cells-derived extracellular vesicles promote proliferation, invasion and migration of osteosarcoma cells via the lncRNA MALAT1/miR-143/NRSN2/Wnt/β-catenin axis. Onco Targets Ther. 2021, 14, 737-749. doi: 10.2147/OTT.S283459 URL
59.	Zhang, H.; Wang, J.; Ren, T.; Huang, Y.; Liang, X.; Yu, Y.; Wang, W.; Niu, J.; Guo, W. Bone marrow mesenchymal stem cell-derived exosomal miR-206 inhibits osteosarcoma progression by targeting TRA2B. Cancer Lett. 2020, 490, 54-65. doi: 10.1016/j.canlet.2020.07.008 URL
60.	Hu, H.; Wang, D.; Li, L.; Yin, H.; He, G.; Zhang, Y. Role of microRNA-335 carried by bone marrow mesenchymal stem cells-derived extracellular vesicles in bone fracture recovery. Cell Death Dis. 2021, 12, 156. doi: 10.1038/s41419-021-03430-3 URL
61.	Katakawa, Y.; Funaba, M.; Murakami, M. Smad8/9 is regulated through the BMP pathway. J Cell Biochem. 2016, 117, 1788-1796. doi: 10.1002/jcb.25478 URL
62.	Xu, T.; Luo, Y.; Wang, J.; Zhang, N.; Gu, C.; Li, L.; Qian, D.; Cai, W.; Fan, J.; Yin, G. Exosomal miRNA-128-3p from mesenchymal stem cells of aged rats regulates osteogenesis and bone fracture healing by targeting Smad5. J Nanobiotechnology. 2020, 18, 47.
63.	Liu, W.; Li, L.; Rong, Y.; Qian, D.; Chen, J.; Zhou, Z.; Luo, Y.; Jiang, D.; Cheng, L.; Zhao, S.; Kong, F.; Wang, J.; Zhou, Z.; Xu, T.; Gong, F.; Huang, Y.; Gu, C.; Zhao, X.; Bai, J.; Wang, F.; Zhao, W.; Zhang, L.; Li, X.; Yin, G.; Fan, J.; Cai, W. Hypoxic mesenchymal stem cell-derived exosomes promote bone fracture healing by the transfer of miR-126. Acta Biomater. 2020, 103, 196-212.
64.	Anam, A. K.; Insogna, K. Update on osteoporosis screening and management. Med Clin North Am. 2021, 105, 1117-1134. doi: 10.1016/j.mcna.2021.05.016 URL
65.	He, X. Y.; Yu, H. M.; Lin, S.; Li, Y. Z. Advances in the application of mesenchymal stem cells, exosomes, biomimetic materials, and 3D printing in osteoporosis treatment. Cell Mol Biol Lett. 2021, 26, 47. doi: 10.1186/s11658-021-00291-8 URL
66.	Liu, P.; Wang, W.; Li, Z.; Li, Y.; Yu, X.; Tu, J.; Zhang, Z. Ferroptosis: a new regulatory mechanism in osteoporosis. Oxid Med Cell Longev. 2022, 2022, 2634431.
67.	Li, Y.; Jin, D.; Xie, W.; Wen, L.; Chen, W.; Xu, J.; Ding, J.; Ren, D.; Xiao, Z. Mesenchymal stem cells-derived exosomes: a possible therapeutic strategy for osteoporosis. Curr Stem Cell Res Ther. 2018, 13, 362-368. doi: 10.2174/1574888X13666180403163456 URL
68.	An, Q.; Wu, D.; Ma, Y.; Zhou, B.; Liu, Q. Suppression of Evi1 promotes the osteogenic differentiation and inhibits the adipogenic differentiation of bone marrow-derived mesenchymal stem cells in vitro. Int J Mol Med. 2015, 36, 1615-1622. doi: 10.3892/ijmm.2015.2385 URL
69.	Wang, Z. X.; Luo, Z. W.; Li, F. X.; Cao, J.; Rao, S. S.; Liu, Y. W.; Wang, Y. Y.; Zhu, G. Q.; Gong, J. S.; Zou, J. T.; Wang, Q.; Tan, Y. J.; Zhang, Y.; Hu, Y.; Li, Y. Y.; Yin, H.; Wang, X. K.; He, Z. H.; Ren, L.; Liu, Z. Z.; Hu, X. K.; Yuan, L. Q.; Xu, R.; Chen, C. Y.; Xie, H. Aged bone matrix-derived extracellular vesicles as a messenger for calcification paradox. Nat Commun. 2022, 13, 1453. doi: 10.1038/s41467-022-29191-x URL
70.	Murali, V. P.; Holmes, C. A. Mesenchymal stromal cell-derived extracellular vesicles for bone regeneration therapy. Bone reports. 2021, 14, 101093. doi: 10.1016/j.bonr.2021.101093 URL
71.	Meng, F.; Xue, X.; Yin, Z.; Gao, F.; Wang, X.; Geng, Z. Research progress of exosomes in bone diseases: mechanism, diagnosis and therapy. Front Bioeng Biotechnol. 2022, 10, 866627.
72.	Peng, Y.; Wu, S.; Li, Y.; Crane, J. L. Type H blood vessels in bone modeling and remodeling. Theranostics. 2020, 10, 426-436. doi: 10.7150/thno.34126 URL
73.	Xie, H.; Cui, Z.; Wang, L.; Xia, Z.; Hu, Y.; Xian, L.; Li, C.; Xie, L.; Crane, J.; Wan, M.; Zhen, G.; Bian, Q.; Yu, B.; Chang, W.; Qiu, T.; Pickarski, M.; Duong, L. T.; Windle, J. J.; Luo, X.; Liao, E.; Cao, X. PDGF-BB secreted by preosteoclasts induces angiogenesis during coupling with osteogenesis. Nat Med. 2014, 20, 1270-1278. doi: 10.1038/nm.3668 URL
74.	Zhang, Y.; Cao, X.; Li, P.; Fan, Y.; Zhang, L.; Ma, X.; Sun, R.; Liu, Y.; Li, W. microRNA-935-modified bone marrow mesenchymal stem cells-derived exosomes enhance osteoblast proliferation and differentiation in osteoporotic rats. Life Sci. 2021, 272, 119204. doi: 10.1016/j.lfs.2021.119204 URL
75.	Yang, Z.; Liu, X.; Zhao, F.; Yao, M.; Lin, Z.; Yang, Z.; Liu, C.; Liu, Y.; Chen, X.; Du, C. Bioactive glass nanoparticles inhibit osteoclast differentiation and osteoporotic bone loss by activating lncRNA NRON expression in the extracellular vesicles derived from bone marrow mesenchymal stem cells. Biomaterials. 2022, 283, 121438. doi: 10.1016/j.biomaterials.2022.121438 URL
76.	Lai, C. P.; Mardini, O.; Ericsson, M.; Prabhakar, S.; Maguire, C.; Chen, J. W.; Tannous, B. A.; Breakefield, X. O. Dynamic biodistribution of extracellular vesicles in vivo using a multimodal imaging reporter. ACS Nano. 2014, 8, 483-494. doi: 10.1021/nn404945r URL
77.	Elsharkasy, O. M.; Nordin, J. Z.; Hagey, D. W.; de Jong, O. G.; Schiffelers, R. M.; Andaloussi, S. E.; Vader, P. Extracellular vesicles as drug delivery systems: why and how? Adv Drug Deliv Rev. 2020, 159, 332-343. doi: 10.1016/j.addr.2020.04.004 URL
78.	Luo, Z. W.; Li, F. X.; Liu, Y. W.; Rao, S. S.; Yin, H.; Huang, J.; Chen, C. Y.; Hu, Y.; Zhang, Y.; Tan, Y. J.; Yuan, L. Q.; Chen, T. H.; Liu, H. M.; Cao, J.; Liu, Z. Z.; Wang, Z. X.; Xie, H. Aptamer-functionalized exosomes from bone marrow stromal cells target bone to promote bone regeneration. Nanoscale. 2019, 11, 20884-20892. doi: 10.1039/C9NR02791B URL
79.	Cui, Y.; Guo, Y.; Kong, L.; Shi, J.; Liu, P.; Li, R.; Geng, Y.; Gao, W.; Zhang, Z.; Fu, D. A bone-targeted engineered exosome platform delivering siRNA to treat osteoporosis. Bioact Mater. 2022, 10, 207-221.
80.	Petek, D.; Hannouche, D.; Suva, D. Osteonecrosis of the femoral head: pathophysiology and current concepts of treatment. EFORT Open Rev. 2019, 4, 85-97. doi: 10.1302/2058-5241.4.180036 URL
81.	Baig, S. A.; Baig, M. N. Osteonecrosis of the femoral head: etiology, investigations, and management. Cureus. 2018, 10, e3171.
82.	Zhang, C.; Su, Y.; Ding, H.; Yin, J.; Zhu, Z.; Song, W. Mesenchymal stem cells-derived and siRNAs-encapsulated exosomes inhibit osteonecrosis of the femoral head. J Cell Mol Med. 2020, 24, 9605-9612. doi: 10.1111/jcmm.15395 URL
83.	Guilak, F.; Nims, R. J.; Dicks, A.; Wu, C. L.; Meulenbelt, I. Osteoarthritis as a disease of the cartilage pericellular matrix. Matrix Biol. 2018, 71-72, 40-50. doi: 10.1016/j.matbio.2018.05.008 URL
84.	Roos, E. M.; Arden, N. K. Strategies for the prevention of knee osteoarthritis. Nat Rev Rheumatol. 2016, 12, 92-101. doi: 10.1038/nrrheum.2015.135 URL
85.	Mianehsaz, E.; Mirzaei, H. R.; Mahjoubin-Tehran, M.; Rezaee, A.; Sahebnasagh, R.; Pourhanifeh, M. H.; Mirzaei, H.; Hamblin, M. R. Mesenchymal stem cell-derived exosomes: a new therapeutic approach to osteoarthritis? Stem Cell Res Ther. 2019, 10, 340. doi: 10.1186/s13287-019-1445-0 URL
86.	Zhu, Y.; Wang, Y.; Zhao, B.; Niu, X.; Hu, B.; Li, Q.; Zhang, J.; Ding, J.; Chen, Y.; Wang, Y. Comparison of exosomes secreted by induced pluripotent stem cell-derived mesenchymal stem cells and synovial membrane-derived mesenchymal stem cells for the treatment of osteoarthritis. Stem Cell Res Ther. 2017, 8, 64. doi: 10.1186/s13287-017-0510-9 URL
87.	Sarhadi, V. K.; Daddali, R.; Seppänen-Kaijansinkko, R. Mesenchymal stem cells and extracellular vesicles in osteosarcoma pathogenesis and therapy. Int J Mol Sci. 2021, 22, 11035. doi: 10.3390/ijms222011035 URL
88.	Xu, X.; Qiu, B.; Yi, P.; Li, H. Overexpression of miR-206 in osteosarcoma and its associated molecular mechanisms as assessed through TCGA and GEO databases. Oncol Lett. 2020, 19, 1751-1758.
89.	Kempf-Bielack, B.; Bielack, S. S.; Jürgens, H.; Branscheid, D.; Berdel, W. E.; Exner, G. U.; Göbel, U.; Helmke, K.; Jundt, G.; Kabisch, H.; Kevric, M.; Klingebiel, T.; Kotz, R.; Maas, R.; Schwarz, R.; Semik, M.; Treuner, J.; Zoubek, A.; Winkler, K. Osteosarcoma relapse after combined modality therapy: an analysis of unselected patients in the Cooperative Osteosarcoma Study Group (COSS). J Clin Oncol. 2005, 23, 559-568. doi: 10.1200/JCO.2005.04.063 URL
90.	Zhao, W.; Qin, P.; Zhang, D.; Cui, X.; Gao, J.; Yu, Z.; Chai, Y.; Wang, J.; Li, J. Long non-coding RNA PVT1 encapsulated in bone marrow mesenchymal stem cell-derived exosomes promotes osteosarcoma growth and metastasis by stabilizing ERG and sponging miR-183-5p. Aging (Albany N Y). 2019, 11, 9581-9596.
91.	He, H.; Ding, M.; Li, T.; Zhao, W.; Zhang, L.; Yin, P.; Zhang, W. Bone mesenchymal stem cell-derived extracellular vesicles containing NORAD promote osteosarcoma by miR-30c-5p. Lab Invest. 2022. doi: 10.1038/s41374-021-00691-6. doi: 10.1038/s41374-021-00691-6 URL
92.	Einhorn, T. A.; Gerstenfeld, L. C. Fracture healing: mechanisms and interventions. Nat Rev Rheumatol. 2015, 11, 45-54. doi: 10.1038/nrrheum.2014.164 URL
93.	Komatsu, D. E.; Warden, S. J. The control of fracture healing and its therapeutic targeting: improving upon nature. J Cell Biochem. 2010, 109, 302-311.
94.	Buettmann, E. G.; McKenzie, J. A.; Migotsky, N.; Sykes, D. A.; Hu, P.; Yoneda, S.; Silva, M. J. VEGFA from early osteoblast lineage cells (Osterix⁺) is required in mice for fracture healing. J Bone Miner Res. 2019, 34, 1690-1706. doi: 10.1002/jbmr.3755 URL
95.	Sun, Y.; Xiong, Y.; Yan, C.; Chen, L.; Chen, D.; Mi, B.; Liu, G. Downregulation of microRNA-16-5p accelerates fracture healing by promoting proliferation and inhibiting apoptosis of osteoblasts in patients with traumatic brain injury. Am J Transl Res. 2019, 11, 4746-4760.
96.	Lin, Z.; Xiong, Y.; Meng, W.; Hu, Y.; Chen, L.; Chen, L.; Xue, H.; Panayi, A. C.; Zhou, W.; Sun, Y.; Cao, F.; Liu, G.; Hu, L.; Yan, C.; Xie, X.; Lin, C.; Cai, K.; Feng, Q.; Mi, B.; Liu, G. Exosomal PD-L1 induces osteogenic differentiation and promotes fracture healing by acting as an immunosuppressant. Bioact Mater. 2022, 13, 300-311.
97.	Tan, S. H. S.; Wong, J. R. Y.; Sim, S. J. Y.; Tjio, C. K. E.; Wong, K. L.; Chew, J. R. J.; Hui, J. H. P.; Toh, W. S. Mesenchymal stem cell exosomes in bone regenerative strategies-a systematic review of preclinical studies. Mater Today Bio. 2020, 7, 100067.
98.	Wang, X.; Thomsen, P. Mesenchymal stem cell-derived small extracellular vesicles and bone regeneration. Basic Clin Pharmacol Toxicol. 2021, 128, 18-36. doi: 10.1111/bcpt.13478 URL
99.	Zhai, M.; Zhu, Y.; Yang, M.; Mao, C. Human mesenchymal stem cell derived exosomes enhance cell-free bone regeneration by altering their miRNAs profiles. Adv Sci (Weinh). 2020, 7, 2001334.
100.	Zhou, X.; Miao, Y.; Wang, Y.; He, S.; Guo, L.; Mao, J.; Chen, M.; Yang, Y.; Zhang, X.; Gan, Y. Tumour-derived extracellular vesicle membrane hybrid lipid nanovesicles enhance siRNA delivery by tumour-homing and intracellular freeway transportation. J Extracell Vesicles. 2022, 11, e12198.
101.	Alqurashi, H.; Ortega Asencio, I.; Lambert, D. W. The emerging potential of extracellular vesicles in cell-free tissue engineering and regenerative medicine. Tissue Eng Part B Rev. 2021, 27, 530-538. doi: 10.1089/ten.teb.2020.0222 URL
102.	Xie, H.; Wang, Z.; Zhang, L.; Lei, Q.; Zhao, A.; Wang, H.; Li, Q.; Cao, Y.; Jie Zhang, W.; Chen, Z. Extracellular vesicle-functionalized decalcified bone matrix scaffolds with enhanced pro-angiogenic and pro-bone regeneration activities. Sci Rep. 2017, 7, 45622. doi: 10.1038/srep45622 URL
103.	Li, W.; Liu, Y.; Zhang, P.; Tang, Y.; Zhou, M.; Jiang, W.; Zhang, X.; Wu, G.; Zhou, Y. Tissue-engineered bone immobilized with human adipose stem cells-derived exosomes promotes bone regeneration. ACS Appl Mater Interfaces. 2018, 10, 5240-5254. doi: 10.1021/acsami.7b17620 URL
104.	Zhang, J.; Liu, X.; Li, H.; Chen, C.; Hu, B.; Niu, X.; Li, Q.; Zhao, B.; Xie, Z.; Wang, Y. Exosomes/tricalcium phosphate combination scaffolds can enhance bone regeneration by activating the PI3K/Akt signaling pathway. Stem Cell Res Ther. 2016, 7, 136. doi: 10.1186/s13287-016-0391-3 URL
105.	Qi, X.; Zhang, J.; Yuan, H.; Xu, Z.; Li, Q.; Niu, X.; Hu, B.; Wang, Y.; Li, X. Exosomes secreted by human-induced pluripotent stem cell-derived mesenchymal stem cells repair critical-sized bone defects through enhanced angiogenesis and osteogenesis in osteoporotic rats. Int J Biol Sci. 2016, 12, 836-849. doi: 10.7150/ijbs.14809 URL
106.	Wang, L.; Wang, J.; Zhou, X.; Sun, J.; Zhu, B.; Duan, C.; Chen, P.; Guo, X.; Zhang, T.; Guo, H. A new self-healing hydrogel containing hucMSC-derived exosomes promotes bone regeneration. Front Bioeng Biotechnol. 2020, 8, 564731. doi: 10.3389/fbioe.2020.564731 URL
107.	Diomede, F.; Gugliandolo, A.; Cardelli, P.; Merciaro, I.; Ettorre, V.; Traini, T.; Bedini, R.; Scionti, D.; Bramanti, A.; Nanci, A.; Caputi, S.; Fontana, A.; Mazzon, E.; Trubiani, O. Three-dimensional printed PLA scaffold and human gingival stem cell-derived extracellular vesicles: a new tool for bone defect repair. Stem Cell Res Ther. 2018, 9, 104. doi: 10.1186/s13287-018-0850-0 URL
108.	Yang, S.; Zhu, B.; Yin, P.; Zhao, L.; Wang, Y.; Fu, Z.; Dang, R.; Xu, J.; Zhang, J.; Wen, N. Integration of human umbilical cord mesenchymal stem cells-derived exosomes with hydroxyapatite-embedded hyaluronic acid-alginate hydrogel for bone regeneration. ACS Biomater Sci Eng. 2020, 6, 1590-1602. doi: 10.1021/acsbiomaterials.9b01363 URL

	Embryonic stem cells	Induced pluripotent stem cells	Somatic or adult stem cells
Source	Inner cell mass of the blastocyst	Reprogrammed somatic cells	Tissue–specific protocols from different tissues
Differentiation potential	Can differentiate into cell types of all three germ lineages	Can differentiate into cell types of all three germ lineages	Can only differentiate into limited cell types
Self–renewal	Complete	Complete	Limited
Proliferative capacity	Strongest	Powerful	Weak and cannot be maintained for a long periods
Tumorigenicity	Yes	Yes	No
Ethical controversy	Yes	No	No

	Embryonic stem cells	Induced pluripotent stem cells	Somatic or adult stem cells
Source	Inner cell mass of the blastocyst	Reprogrammed somatic cells	Tissue–specific protocols from different tissues
Differentiation potential	Can differentiate into cell types of all three germ lineages	Can differentiate into cell types of all three germ lineages	Can only differentiate into limited cell types
Self–renewal	Complete	Complete	Limited
Proliferative capacity	Strongest	Powerful	Weak and cannot be maintained for a long periods
Tumorigenicity	Yes	Yes	No
Ethical controversy	Yes	No	No

Vesicles	Size (nm)	Density (g/mL)	Origin	Markers	Membrane permeability
Exosomes	30–150	1.13–1.18	Endosomes	Tetraspanins (CD9, CD63, CD81), TSG101, ALIX	Impermeable
Microvesicles	200–1000	1.16–1.19	Budding of plasma membrane	Integrins, selectins, CD40	Impermeable
Apoptotic bodies	>1000	1.16–1.28	Release after apoptosis	Propidium iodide positive Phosphatidylserine DNA fragmentation	Permeable

Vesicles	Size (nm)	Density (g/mL)	Origin	Markers	Membrane permeability
Exosomes	30–150	1.13–1.18	Endosomes	Tetraspanins (CD9, CD63, CD81), TSG101, ALIX	Impermeable
Microvesicles	200–1000	1.16–1.19	Budding of plasma membrane	Integrins, selectins, CD40	Impermeable
Apoptotic bodies	>1000	1.16–1.28	Release after apoptosis	Propidium iodide positive Phosphatidylserine DNA fragmentation	Permeable

Diseases	Source of EVs	Main contents of EVs	Main mechanism	Effect	Reference
OP	BMSCs	lncRNA MALAT1	Sponge miR–34c, upregulate SATB2	Alleviates OP	44
OP	BMSCs	miRNA–150–3p	Promote osteoblast proliferation and differentiation	Mitigate OP	45
OP	BMSCs	GPNMB	Activate Wnt/β–catenin signalling	Alleviate OP	46
OP	BMSCs	miR–188	Promote osteogenesis and inhibit adipogenic differentiation	Alleviate OP	47
OP	BMSCs from OVX mice	miR–214–3p	Inhibit type H vessel formation, and bone mineral density and contents	Aggravate OP	48
ONFH	GC–treated BMSCs	miR–451	Increase the level of PAI–1	Aggravate ONFH	49, 50
ONFH	BMSCs	miR–122–5p	RTK/Ras/MAPK signalling pathway	Promote ONFH healing	51
ONFH	hUCMSCs	miR–21	PTEN–AKT pathway	Promote ONFH healing	52
OA	SMSCs	Wnt5a and Wnt5b	Activate the YAP signalling pathway	Alleviate OA	53
OA	Ad–MSCs	Unknown	Inhibit inflammation and MMP activity	Alleviate OA	54
OA	MSCIPFP	miR–100–5p	Inhibit mTOR signalling	Alleviate OA	55
OS	Ad–MSCs	Unknown	Promote osteosarcoma cell invasion, migration, and proliferation	Promote OS progression	56
OS	BMSCs	hsa–miR–148a	Promote OS cell proliferation, metastasis and prevent apoptosis	Promote OS progression	57
OS	BMSCs	lncRNA MALAT1	lncRNA MALAT1/miR–143/NRSN2/Wnt/β–catenin pathway	Promote OS progression	58
OS	BMSCs	miR–206	miR–206/TRA2B	Suppress OS progression	59
BF	BMSCs	miR–335	miR–335/VapB/Wnt/β–catenin pathway	Promoted BF recovery	60
BF	Aged–BMSCs	miR–128–3p	miR–128–3p/Smad8 pathway	Inhibition of BF healing	61, 62
BF	BMSCs	miR–126	SPRED1/Ras/Erk pathway	Promoted BF recovery	63

Mesenchymal stem cell–derived extracellular vesicles: a possible therapeutic strategy for orthopaedic diseases: a narrative review

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Source of extracellular vesicles	Extracellular vesicle modification	Scaffolds	Main function	Reference
hMSCs	Osteoinduction	3D–printed titanium alloy scaffolds	Induce osteogenic differentiation of hMSCs	99
BMSCs	Osteoinduction	Functionalised decalcified bone matrix scaffolds	Pro–angiogenic and pro–osteogenic regeneration	102
hASCs	Osteoinduction	Polydopamine–coating PLGA scaffolds	Enhance the migration, proliferation and osteogenic differentiation of hBMSCs	103
hiPS–MSCs	–	Exosome/β–TCP combination scaffold	Activating the PI3K/Akt signalling pathway and promoting osteogenic differentiation	104
hiPS–MSCs	–	β–TCP scaffolds	Pro–angiogenic and pro–osteogenic differentiation	105
hucMSCs	–	CHA/SF/GCS/DF–PEG hydrogel	Promote osteogenic differentiation	106
hGMSCs	–	3D–PLA scaffolds	Promote osteogenic differentiation	107
hucMSCs	–	HA–ALG hydrogel scaffolds	Promote the proliferation, migration, and osteogenic differentiation	108

NCT No.	Title	Status	Phase	Disease	Aim	Intervention/treatment	Source of extracellular vesicles	Sponsor/collaborator
NCT04223622	Effects of ASC secretome on human osteochondral explants	Recruiting	Phase I	Osteoarthritis	Development of treatment strategies	Not clear	Adipose–derived stromal cells	Istituto Ortopedico Galeazzi, Italy
NCT05060107	Intra–articular injection of MSC–derived exosomes in knee osteoarthritis	Not yet recruiting	Phase I	Osteoarthritis	Development of treatment strategies	Intra–articular knee injection	Allogeneic mesenchymal stromal cells	Francisco Espinoza, Universidad de los Andes, Chile
NCT05101655	Construction of microfluidic exosome chip for diagnosis of lung metastasis of osteosarcoma	Enrolling by invitation	–	Osteosarcoma	Development of diagnostic markers	–	Plasma	Ruijin Hospital, China
NCT03108677	Circulating exosome RNA in lung metastases of primary high–grade osteosarcoma	Recruiting	–	Osteosarcoma	Development of diagnostic markers	–	Plasma	Ruijin Hospital, China

[1]	Ricardo Donate, Maryam Tamaddon, Viviana Ribeiro, Mario Monzón, J. Miguel Oliveira, Chaozong Liu. Translation through collaboration: practice applied in BAMOS project in in vivo testing of innovative osteochondral scaffolds [J]. Biomaterials Translational, 2022, 3(2): 102-104.
[2]	Maryam Tamaddon, Helena Gilja, Ling Wang, J. Miguel Oliveira, Xiaodan Sun, Rongwei Tan, Chaozong Liu. Osteochondral scaffolds for early treatment of cartilage defects in osteoarthritic joints: from bench to clinic [J]. Biomaterials Translational, 2020, 1(1): 3-17.
[3]	Xing Yang, Yuanyuan Li, Xujie Liu, Wei He, Qianli Huang, Qingling Feng. Nanoparticles and their effects on differentiation of mesenchymal stem cells [J]. Biomaterials Translational, 2020, 1(1): 58-68.