The role of extracellular vesicles in bone metastasis

Multiple types of cancer have the specific ability to home to the bone microenvironment and cause metastatic lesions. Despite being the focus of intense investigation, the molecular and cellular mechanisms that regulate the metastasis of disseminated tumor cells still remain largely unknown. Bone metastases severely impact quality of life since they are associated with pain, fractures, and bone marrow aplasia. In this review, we will summarize the recent discoveries on the role of extracellular vesicles (EV) in the regulation of bone remodeling activity and bone metastasis occurrence. Indeed, it was shown that extracellular vesicles, including exosomes and microvesicles, released from tumor cells can modify the bone microenvironment, allowing the formation of osteolytic, osteosclerotic, and mixed mestastases. In turn, bone-derived EV can stimulate the proliferation of tumor cells. The inhibition of EV-mediated crosstalk between cancer and bone cells could represent a new therapeutic target for bone metastasis

Microvesicles as vehicles for tissue regeneration: Changing of the guards

Purpose of Review: Microvesicles (MVs) have been recognised as mediators of stem cell function, enabling and guiding their regenerative effects. Recent Findings: MVs constitute one unique size class of extracellular vesicles (EVs) directly shed from the cell plasma membrane. They facilitate cell-to-cell communication via intercellular transfer of proteins, mRNA and microRNA (miRNA). MVs derived from stem cells, or stem cell regulatory cell types, have proven roles in tissue regeneration and repair processes. Their role in the maintenance of healthy tissue function throughout the life course and thus in age related health span remains to be elucidated. Summary: Understanding the biogenesis and mechanisms of action of MVs may enable the development of cell-free therapeutics capable of assisting in tissue maintenance and repair for a variety of age-related degenerative diseases. This review critically evaluates recent work published in this area and highlights important new findings demonstrating the use of MVs in tissue regeneration

Extracellular vesicles, ageing, and therapeutic interventions

A more comprehensive understanding of the human ageing process is required to help mitigate the increasing burden of age-related morbidities in a rapidly growing global demographic of elderly individuals. One exciting novel strategy that has emerged to intervene involves the use of extracellular vesicles to engender tissue regeneration. Specifically, this employs their molecular payloads to confer changes in the epigenetic landscape of ageing cells and ameliorate the loss of functional capacity. Understanding the biology of extracellular vesicles and the specific roles they play during normative ageing will allow for the development of novel cell-free therapeutic interventions. Hence, the purpose of this review is to summarise the current understanding of the mechanisms that drive ageing, critically explore how extracellular vesicles affect ageing processes and discuss their therapeutic potential to mitigate the effects of age-associated morbidities and improve the human health span

Extracellular Vesicles from Mesenchymal Stem Cells as Novel Treatments for Musculoskeletal Diseases

[EN] Mesenchymal stem/stromal cells (MSCs) represent a promising therapy for musculoskeletal diseases. There is compelling evidence indicating that MSC effects are mainly mediated by paracrine mechanisms and in particular by the secretion of extracellular vesicles (EVs). Many studies have thus suggested that EVs may be an alternative to cell therapy with MSCs in tissue repair. In this review, we summarize the current understanding of MSC EVs actions in preclinical studies of (1) immune regulation and rheumatoid arthritis, (2) bone repair and bone diseases, (3) cartilage repair and osteoarthritis, (4) intervertebral disk degeneration and (5) skeletal muscle and tendon repair. We also discuss the mechanisms underlying these actions and the perspectives of MSC EVs-based strategies for future treatments of musculoskeletal disorders.This work has been funded by grant SAF2017-85806-R (Ministerio de Ciencia, Innovación y Universidades, Spain, FEDER.Alcaraz Tormo, MJ.; Compañ, Á.; Guillem Salazar, MI. (2019). Extracellular Vesicles from Mesenchymal Stem Cells as Novel Treatments for Musculoskeletal Diseases. Cells. 9(1):1-21. https://doi.org/10.3390/cells9010098S12191Musculoskeletal Conditions https://www.who. int/news-room/fact-sheets/detail/musculoskeletal-conditionsHofer, H. R., & Tuan, R. S. (2016). Secreted trophic factors of mesenchymal stem cells support neurovascular and musculoskeletal therapies. Stem Cell Research & Therapy, 7(1). doi:10.1186/s13287-016-0394-0Wang, L., Wang, L., Cong, X., Liu, G., Zhou, J., Bai, B., … Liu, Y. (2013). Human Umbilical Cord Mesenchymal Stem Cell Therapy for Patients with Active Rheumatoid Arthritis: Safety and Efficacy. Stem Cells and Development, 22(24), 3192-3202. doi:10.1089/scd.2013.0023Franceschetti, T., & De Bari, C. (2017). The potential role of adult stem cells in the management of the rheumatic diseases. Therapeutic Advances in Musculoskeletal Disease, 9(7), 165-179. doi:10.1177/1759720x17704639Freitag, J., Bates, D., Boyd, R., Shah, K., Barnard, A., Huguenin, L., & Tenen, A. (2016). Mesenchymal stem cell therapy in the treatment of osteoarthritis: reparative pathways, safety and efficacy – a review. BMC Musculoskeletal Disorders, 17(1). doi:10.1186/s12891-016-1085-9Vega, A., Martín-Ferrero, M. A., Del Canto, F., Alberca, M., García, V., Munar, A., … García-Sancho, J. (2015). Treatment of Knee Osteoarthritis With Allogeneic Bone Marrow Mesenchymal Stem Cells. Transplantation, 99(8), 1681-1690. doi:10.1097/tp.0000000000000678Cui, G.-H., Wang, Y. Y., Li, C.-J., Shi, C.-H., & Wang, W.-S. (2016). Efficacy of mesenchymal stem cells in treating patients with osteoarthritis of the knee: A meta-analysis. Experimental and Therapeutic Medicine, 12(5), 3390-3400. doi:10.3892/etm.2016.3791Iaquinta, M. R., Mazzoni, E., Bononi, I., Rotondo, J. C., Mazziotta, C., Montesi, M., … Martini, F. (2019). Adult Stem Cells for Bone Regeneration and Repair. Frontiers in Cell and Developmental Biology, 7. doi:10.3389/fcell.2019.00268Marolt Presen, D., Traweger, A., Gimona, M., & Redl, H. (2019). Mesenchymal Stromal Cell-Based Bone Regeneration Therapies: From Cell Transplantation and Tissue Engineering to Therapeutic Secretomes and Extracellular Vesicles. Frontiers in Bioengineering and Biotechnology, 7. doi:10.3389/fbioe.2019.00352Jo, C. H., Chai, J. W., Jeong, E. C., Oh, S., & Yoon, K. S. (2020). Intratendinous Injection of Mesenchymal Stem Cells for the Treatment of Rotator Cuff Disease: A 2-Year Follow-Up Study. Arthroscopy: The Journal of Arthroscopic & Related Surgery, 36(4), 971-980. doi:10.1016/j.arthro.2019.11.120Klimczak, A., Kozlowska, U., & Kurpisz, M. (2018). Muscle Stem/Progenitor Cells and Mesenchymal Stem Cells of Bone Marrow Origin for Skeletal Muscle Regeneration in Muscular Dystrophies. Archivum Immunologiae et Therapiae Experimentalis, 66(5), 341-354. doi:10.1007/s00005-018-0509-7Ferreira, J. R., Teixeira, G. Q., Santos, S. G., Barbosa, M. A., Almeida-Porada, G., & Gonçalves, R. M. (2018). Mesenchymal Stromal Cell Secretome: Influencing Therapeutic Potential by Cellular Pre-conditioning. Frontiers in Immunology, 9. doi:10.3389/fimmu.2018.02837Aggarwal, S., & Pittenger, M. F. (2005). Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood, 105(4), 1815-1822. doi:10.1182/blood-2004-04-1559Ren, G., Zhang, L., Zhao, X., Xu, G., Zhang, Y., Roberts, A. I., … Shi, Y. (2008). Mesenchymal Stem Cell-Mediated Immunosuppression Occurs via Concerted Action of Chemokines and Nitric Oxide. Cell Stem Cell, 2(2), 141-150. doi:10.1016/j.stem.2007.11.014Chabannes, D., Hill, M., Merieau, E., Rossignol, J., Brion, R., Soulillou, J. P., … Cuturi, M. C. (2007). A role for heme oxygenase-1 in the immunosuppressive effect of adult rat and human mesenchymal stem cells. Blood, 110(10), 3691-3694. doi:10.1182/blood-2007-02-075481Bernardo, M. E., & Fibbe, W. E. (2013). Mesenchymal Stromal Cells: Sensors and Switchers of Inflammation. Cell Stem Cell, 13(4), 392-402. doi:10.1016/j.stem.2013.09.006Selmani, Z., Naji, A., Zidi, I., Favier, B., Gaiffe, E., Obert, L., … Deschaseaux, F. (2008). Human Leukocyte Antigen-G5 Secretion by Human Mesenchymal Stem Cells Is Required to Suppress T Lymphocyte and Natural Killer Function and to Induce CD4+CD25highFOXP3+Regulatory T Cells. Stem Cells, 26(1), 212-222. doi:10.1634/stemcells.2007-0554Di Nicola, M., Carlo-Stella, C., Magni, M., Milanesi, M., Longoni, P. D., Matteucci, P., … Gianni, A. M. (2002). Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood, 99(10), 3838-3843. doi:10.1182/blood.v99.10.3838Gunawardena, T. N. A., Rahman, M. T., Abdullah, B. J. J., & Abu Kasim, N. H. (2019). Conditioned media derived from mesenchymal stem cell cultures: The next generation for regenerative medicine. Journal of Tissue Engineering and Regenerative Medicine, 13(4), 569-586. doi:10.1002/term.2806Arslan, F., Lai, R. C., Smeets, M. B., Akeroyd, L., Choo, A., Aguor, E. N. E., … de Kleijn, D. P. (2013). Mesenchymal stem cell-derived exosomes increase ATP levels, decrease oxidative stress and activate PI3K/Akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia/reperfusion injury. Stem Cell Research, 10(3), 301-312. doi:10.1016/j.scr.2013.01.002Tian, T., Wang, Y., Wang, H., Zhu, Z., & Xiao, Z. (2010). Visualizing of the cellular uptake and intracellular trafficking of exosomes by live-cell microscopy. Journal of Cellular Biochemistry, 111(2), 488-496. doi:10.1002/jcb.22733Feng, D., Zhao, W.-L., Ye, Y.-Y., Bai, X.-C., Liu, R.-Q., Chang, L.-F., … Sui, S.-F. (2010). Cellular Internalization of Exosomes Occurs Through Phagocytosis. Traffic, 11(5), 675-687. doi:10.1111/j.1600-0854.2010.01041.xXu, J., Wang, Y., Hsu, C.-Y., Gao, Y., Meyers, C. A., Chang, L., … James, A. W. (2019). Human perivascular stem cell-derived extracellular vesicles mediate bone repair. eLife, 8. doi:10.7554/elife.48191Morrison, T. J., Jackson, M. V., Cunningham, E. K., Kissenpfennig, A., McAuley, D. F., O’Kane, C. M., & Krasnodembskaya, A. D. (2017). Mesenchymal Stromal Cells Modulate Macrophages in Clinically Relevant Lung Injury Models by Extracellular Vesicle Mitochondrial Transfer. American Journal of Respiratory and Critical Care Medicine, 196(10), 1275-1286. doi:10.1164/rccm.201701-0170ocLener, T., Gimona, M., Aigner, L., Börger, V., Buzas, E., Camussi, G., … Portillo, H. A. del. (2015). Applying extracellular vesicles based therapeutics in clinical trials – an ISEV position paper. Journal of Extracellular Vesicles, 4(1), 30087. doi:10.3402/jev.v4.30087Raposo, G., & Stoorvogel, W. (2013). Extracellular vesicles: Exosomes, microvesicles, and friends. Journal of Cell Biology, 200(4), 373-383. doi:10.1083/jcb.201211138Qiu, G., Zheng, G., Ge, M., Wang, J., Huang, R., Shu, Q., & Xu, J. (2018). Mesenchymal stem cell-derived extracellular vesicles affect disease outcomes via transfer of microRNAs. Stem Cell Research & Therapy, 9(1). doi:10.1186/s13287-018-1069-9Van Niel, G., D’Angelo, G., & Raposo, G. (2018). Shedding light on the cell biology of extracellular vesicles. Nature Reviews Molecular Cell Biology, 19(4), 213-228. doi:10.1038/nrm.2017.125Lai, R. C., Tan, S. S., Yeo, R. W. Y., Choo, A. B. H., Reiner, A. T., Su, Y., … Lim, S. K. (2016). MSC secretes at least 3 EV types each with a unique permutation of membrane lipid, protein and RNA. Journal of Extracellular Vesicles, 5(1), 29828. doi:10.3402/jev.v5.29828Théry, C., Witwer, K. W., Aikawa, E., Alcaraz, M. J., Anderson, J. D., Andriantsitohaina, R., … Atkin-Smith, G. K. (2018). Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. Journal of Extracellular Vesicles, 7(1), 1535750. doi:10.1080/20013078.2018.1535750Tofiño-Vian, M., Guillén, M. I., & Alcaraz, M. J. (2018). Extracellular vesicles: A new therapeutic strategy for joint conditions. Biochemical Pharmacology, 153, 134-146. doi:10.1016/j.bcp.2018.02.004Wong, D. E., Banyard, D. A., Santos, P. J. F., Sayadi, L. R., Evans, G. R. D., & Widgerow, A. D. (2019). Adipose-derived stem cell extracellular vesicles: A systematic review✰. Journal of Plastic, Reconstructive & Aesthetic Surgery, 72(7), 1207-1218. doi:10.1016/j.bjps.2019.03.008Zhou, Y., Xu, H., Xu, W., Wang, B., Wu, H., Tao, Y., … Qian, H. (2013). Exosomes released by human umbilical cord mesenchymal stem cells protect against cisplatin-induced renal oxidative stress and apoptosis in vivo and in vitro. Stem Cell Research & Therapy, 4(2), 34. doi:10.1186/scrt194De Jong, O. G., Van Balkom, B. W. M., Schiffelers, R. M., Bouten, C. V. C., & Verhaar, M. C. (2014). Extracellular Vesicles: Potential Roles in Regenerative Medicine. Frontiers in Immunology, 5. doi:10.3389/fimmu.2014.00608Robbins, P. D., & Morelli, A. E. (2014). Regulation of immune responses by extracellular vesicles. Nature Reviews Immunology, 14(3), 195-208. doi:10.1038/nri3622Burrello, J., Monticone, S., Gai, C., Gomez, Y., Kholia, S., & Camussi, G. (2016). Stem Cell-Derived Extracellular Vesicles and Immune-Modulation. Frontiers in Cell and Developmental Biology, 4. doi:10.3389/fcell.2016.00083Siegel, G., Schäfer, R., & Dazzi, F. (2009). The Immunosuppressive Properties of Mesenchymal Stem Cells. Transplantation, 87(Supplement), S45-S49. doi:10.1097/tp.0b013e3181a285b0Fierabracci, A., Del Fattore, A., Luciano, R., Muraca, M., Teti, A., & Muraca, M. (2015). Recent Advances in Mesenchymal Stem Cell Immunomodulation: The Role of Microvesicles. Cell Transplantation, 24(2), 133-149. doi:10.3727/096368913x675728Mokarizadeh, A., Delirezh, N., Morshedi, A., Mosayebi, G., Farshid, A.-A., & Mardani, K. (2012). Microvesicles derived from mesenchymal stem cells: Potent organelles for induction of tolerogenic signaling. Immunology Letters, 147(1-2), 47-54. doi:10.1016/j.imlet.2012.06.001Conforti, A., Scarsella, M., Starc, N., Giorda, E., Biagini, S., Proia, A., … Bernardo, M. E. (2014). Microvescicles Derived from Mesenchymal Stromal Cells Are Not as Effective as Their Cellular Counterpart in the Ability to Modulate Immune Responses In Vitro. Stem Cells and Development, 23(21), 2591-2599. doi:10.1089/scd.2014.0091Carreras-Planella, L., Monguió-Tortajada, M., Borràs, F. E., & Franquesa, M. (2019). Immunomodulatory Effect of MSC on B Cells Is Independent of Secreted Extracellular Vesicles. Frontiers in Immunology, 10. doi:10.3389/fimmu.2019.01288Chen, W., Huang, Y., Han, J., Yu, L., Li, Y., Lu, Z., … Xiao, Y. (2016). Immunomodulatory effects of mesenchymal stromal cells-derived exosome. Immunologic Research, 64(4), 831-840. doi:10.1007/s12026-016-8798-6Harting, M. T., Srivastava, A. K., Zhaorigetu, S., Bair, H., Prabhakara, K. S., Toledano Furman, N. E., … Olson, S. D. (2017). Inflammation-Stimulated Mesenchymal Stromal Cell-Derived Extracellular Vesicles Attenuate Inflammation. STEM CELLS, 36(1), 79-90. doi:10.1002/stem.2730Reis, M., Mavin, E., Nicholson, L., Green, K., Dickinson, A. M., & Wang, X. (2018). Mesenchymal Stromal Cell-Derived Extracellular Vesicles Attenuate Dendritic Cell Maturation and Function. Frontiers in Immunology, 9. doi:10.3389/fimmu.2018.02538Ji, L., Bao, L., Gu, Z., Zhou, Q., Liang, Y., Zheng, Y., … Feng, X. (2019). Comparison of immunomodulatory properties of exosomes derived from bone marrow mesenchymal stem cells and dental pulp stem cells. Immunologic Research, 67(4-5), 432-442. doi:10.1007/s12026-019-09088-6Blazquez, R., Sanchez-Margallo, F. M., de la Rosa, O., Dalemans, W., Ã lvarez, V., Tarazona, R., & Casado, J. G. (2014). Immunomodulatory Potential of Human Adipose Mesenchymal Stem Cells Derived Exosomes on in vitro Stimulated T Cells. Frontiers in Immunology, 5. doi:10.3389/fimmu.2014.00556Zhang, B., Yin, Y., Lai, R. C., Tan, S. S., Choo, A. B. H., & Lim, S. K. (2014). Mesenchymal Stem Cells Secrete Immunologically Active Exosomes. Stem Cells and Development, 23(11), 1233-1244. doi:10.1089/scd.2013.0479Zhang, B., Yeo, R. W. Y., Lai, R. C., Sim, E. W. K., Chin, K. C., & Lim, S. K. (2018). Mesenchymal stromal cell exosome–enhanced regulatory T-cell production through an antigen-presenting cell–mediated pathway. Cytotherapy, 20(5), 687-696. doi:10.1016/j.jcyt.2018.02.372TOH, W. S., ZHANG, B., LAI, R. C., & LIM, S. K. (2018). Immune regulatory targets of mesenchymal stromal cell exosomes/small extracellular vesicles in tissue regeneration. Cytotherapy, 20(12), 1419-1426. doi:10.1016/j.jcyt.2018.09.008Budoni, M., Fierabracci, A., Luciano, R., Petrini, S., Di Ciommo, V., & Muraca, M. (2013). The Immunosuppressive Effect of Mesenchymal Stromal Cells on B Lymphocytes is Mediated by Membrane Vesicles. Cell Transplantation, 22(2), 369-379. doi:10.3727/096368911x582769bDi Trapani, M., Bassi, G., Midolo, M., Gatti, A., Takam Kamga, P., Cassaro, A., … Krampera, M. (2016). Differential and transferable modulatory effects of mesenchymal stromal cell-derived extracellular vesicles on T, B and NK cell functions. Scientific Reports, 6(1). doi:10.1038/srep24120Henao Agudelo, J. S., Braga, T. T., Amano, M. T., Cenedeze, M. A., Cavinato, R. A., Peixoto-Santos, A. R., … Camara, N. O. S. (2017). Mesenchymal Stromal Cell-Derived Microvesicles Regulate an Internal Pro-Inflammatory Program in Activated Macrophages. Frontiers in Immunology, 8. doi:10.3389/fimmu.2017.00881Lo Sicco, C., Reverberi, D., Balbi, C., Ulivi, V., Principi, E., Pascucci, L., … Tasso, R. (2017). Mesenchymal Stem Cell-Derived Extracellular Vesicles as Mediators of Anti-Inflammatory Effects: Endorsement of Macrophage Polarization. STEM CELLS Translational Medicine, 6(3), 1018-1028. doi:10.1002/sctm.16-0363Ti, D., Hao, H., Tong, C., Liu, J., Dong, L., Zheng, J., … Han, W. (2015). LPS-preconditioned mesenchymal stromal cells modify macrophage polarization for resolution of chronic inflammation via exosome-shuttled let-7b. Journal of Translational Medicine, 13(1). doi:10.1186/s12967-015-0642-6Firestein, G. S. (2003). Evolving concepts of rheumatoid arthritis. Nature, 423(6937), 356-361. doi:10.1038/nature01661Goronzy, J. J., & Weyand, C. M. (2009). Developments in the scientific understanding of rheumatoid arthritis. Arthritis Research & Therapy, 11(5), 249. doi:10.1186/ar2758Casado, J. G., Blázquez, R., Vela, F. J., Álvarez, V., Tarazona, R., & Sánchez-Margallo, F. M. (2017). Mesenchymal Stem Cell-Derived Exosomes: Immunomodulatory Evaluation in an Antigen-Induced Synovitis Porcine Model. Frontiers in Veterinary Science, 4. doi:10.3389/fvets.2017.00039Cosenza, S., Toupet, K., Maumus, M., Luz-Crawford, P., Blanc-Brude, O., Jorgensen, C., & Noël, D. (2018). Mesenchymal stem cells-derived exosomes are more immunosuppressive than microparticles in inflammatory arthritis. Theranostics, 8(5), 1399-1410. doi:10.7150/thno.21072Yang, Y., Hutchinson, P., & Morand, E. F. (1999). Inhibitory effect of annexin I on synovial inflammation in rat adjuvant arthritis. Arthritis & Rheumatism, 42(7), 1538-1544. doi:10.1002/1529-0131(199907)42:73.0.co;2-3Headland, S. E., Jones, H. R., Norling, L. V., Kim, A., Souza, P. R., Corsiero, E., … Perretti, M. (2015). Neutrophil-derived microvesicles enter cartilage and protect the joint in inflammatory arthritis. Science Translational Medicine, 7(315), 315ra190-315ra190. doi:10.1126/scitranslmed.aac5608Tofiño-Vian, M., Guillén, M. I., Pérez del Caz, M. D., Silvestre, A., & Alcaraz, M. J. (2018). Microvesicles from Human Adipose Tissue-Derived Mesenchymal Stem Cells as a New Protective Strategy in Osteoarthritic Chondrocytes. Cellular Physiology and Biochemistry, 47(1), 11-25. doi:10.1159/000489739Ando, Y., Matsubara, K., Ishikawa, J., Fujio, M., Shohara, R., Hibi, H., … Yamamoto, A. (2014). Stem cell-conditioned medium accelerates distraction osteogenesis through multiple regenerative mechanisms. Bone, 61, 82-90. doi:10.1016/j.bone.2013.12.029Lu, Z., Chen, Y., Dunstan, C., Roohani-Esfahani, S., & Zreiqat, H. (2017). Priming Adipose Stem Cells with Tumor Necrosis Factor-Alpha Preconditioning Potentiates Their Exosome Efficacy for Bone Regeneration. Tissue Engineering Part A, 23(21-22), 1212-1220. doi:10.1089/ten.tea.2016.0548Qin, Y., Wang, L., Gao, Z., Chen, G., & Zhang, C. (2016). Bone marrow stromal/stem cell-derived extracellular vesicles regulate osteoblast activity and differentiation in vitro and promote bone regeneration in vivo. Scientific Reports, 6(1). doi:10.1038/srep21961Wang, X., Omar, O., Vazirisani, F., Thomsen, P., & Ekström, K. (2018). Mesenchymal stem cell-derived exosomes have altered microRNA profiles and induce osteogenic differentiation depending on the stage of differentiation. PLOS ONE, 13(2), e0193059. doi:10.1371/journal.pone.0193059Shirley, D., Marsh, D., Jordan, G., McQuaid, S., & Li, G. (2005). Systemic recruitment of osteoblastic cells in fracture healing. Journal of Orthopaedic Research, 23(5), 1013-1021. doi:10.1016/j.orthres.2005.01.013Lee, D. Y., Cho, T.-J., Kim, J. A., Lee, H. R., Yoo, W. J., Chung, C. Y., & Choi, I. H. (2008). Mobilization of endothelial progenitor cells in fracture healing and distraction osteogenesis. Bone, 42(5), 932-941. doi:10.1016/j.bone.2008.01.007Furuta, T., Miyaki, S., Ishitobi, H., Ogura, T., Kato, Y., Kamei, N., … Ochi, M. (2016). Mesenchymal Stem Cell-Derived Exosomes Promote Fracture Healing in a Mouse Model. STEM CELLS Translational Medicine, 5(12), 1620-1630. doi:10.5966/sctm.2015-0285Li, W., Liu, Y., Zhang, P., Tang, Y., Zhou, M., Jiang, W., … Zhou, Y. (2018). Tissue-Engineered Bone Immobilized with Human Adipose Stem Cells-Derived Exosomes Promotes Bone Regeneration. ACS Applied Materials & Interfaces, 10(6), 5240-5254. doi:10.1021/acsami.7b17620Hirschi, K. K., Li, S., & Roy, K. (2014). Induced Pluripotent Stem Cells for Regenerative Medicine. Annual Review of Biomedical Engineering, 16(1), 277-294. doi:10.1146/annurev-bioeng-071813-105108Sabapathy, V., & Kumar, S. (2016). hi PSC ‐derived iMSC s: NextGen MSC s as an advanced therapeutically active cell resource for regenerative medicine. Journal of Cellular and Molecular Medicine, 20(8), 1571-1588. doi:10.1111/jcmm.12839Zhang, J., Liu, X., Li, H., Chen, C., Hu, B., Niu, X., … Wang, Y. (2016). Exosomes/tricalcium phosphate combination scaffolds can enhance bone regeneration by activating the PI3K/Akt signaling pathway. Stem Cell Research & Therapy, 7(1). doi:10.1186/s13287-016-0391-3Narayanan, R., Huang, C.-C., & Ravindran, S. (2016). Hijacking the Cellular Mail: Exosome Mediated Differentiation of Mesenchymal Stem Cells. Stem Cells International, 2016, 1-11. doi:10.1155/2016/3808674Zhu, Y., Jia, Y., Wang, Y., Xu, J., & Chai, Y. (2019). Impaired Bone Regenerative Effect of Exosomes Derived from Bone Marrow Mesenchymal Stem Cells in Type 1 Diabetes. STEM CELLS Translational Medicine, 8(6), 593-605. doi:10.1002/sctm.18-0199Ferreira, E., & Porter, R. M. (2018). Harnessing extracellular vesicles to direct endochondral repair of large bone defects. Bone & Joint Research, 7(4), 263-273. doi:10.1302/2046-3758.74.bjr-2018-0006Moya, A., Paquet, J., Deschepper, M., Larochette, N., Oudina, K., Denoeud, C., … Petite, H. (2018). Human Mesenchymal Stem Cell Failure to Adapt to Glucose Shortage and Rapidly Use Intracellular Energy Reserves Through Glycolysis Explains Poor Cell Survival After Implantation. STEM CELLS, 36(3), 363-376. doi:10.1002/stem.2763Moya, A., Larochette, N., Paquet, J., Deschepper, M., Bensidhoum, M., Izzo, V., … Logeart-Avramoglou, D. (2016). Quiescence Preconditioned Human Multipotent Stromal Cells Adopt a Metabolic Profile Favorable for Enhanced Survival under Ischemia. STEM CELLS, 35(1), 181-196. doi:10.1002/stem.2493Potier, E., Ferreira, E., Andriamanalijaona, R., Pujol, J.-P., Oudina, K., Logeart-Avramoglou, D., & Petite, H. (2007). Hypoxia affects mesenchymal stromal cell osteogenic differentiation and angiogenic factor expression. Bone, 40(4), 1078-1087. doi:10.1016/j.bone.2006.11.024Jia, Y., Zhu, Y., Qiu, S., Xu, J., & Chai, Y. (2019). Exosomes secreted by endothelial progenitor cells accelerate bone regeneration during distraction osteogenesis by stimulating angiogenesis. Stem Cell Research & Therapy, 10(1). doi:10.1186/s13287-018-1115-7Zhang, Y., Hao, Z., Wang, P., Xia, Y., Wu, J., Xia, D., … Xu, S. (2019). Exosomes from human umbilical cord mesenchymal stem cells enhance fracture healing through HIF‐1α‐mediated promotion of angiogenesis in a rat model of stabilized fracture. Cell Proliferation, 52(2), e12570. doi:10.1111/cpr.12570Qi, X., Zhang, J., Yuan, H., Xu, Z., Li, Q., Niu, X., … Li, X. (2016). Exosomes Secreted by Human-Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Repair Critical-Sized Bone De

Extracellular Vesicles in Musculoskeletal Pathologies and Regeneration

The incidence of musculoskeletal diseases is steadily increasing with aging of the population. In the past years, extracellular vesicles (EVs) have gained attention in musculoskeletal research. EVs have been associated with various musculoskeletal pathologies as well as suggested as treatment option. EVs play a pivotal role in communication between cells and their environment. Thereby, the EV cargo is highly dependent on their cellular origin. In this review, we summarize putative mechanisms by which EVs can contribute to musculoskeletal tissue homeostasis, regeneration and disease, in particular matrix remodeling and mineralization, pro-angiogenic effects and immunomodulatory activities. Mesenchymal stromal cells (MSCs) present the most frequently used cell source for EV generation for musculoskeletal applications, and herein we discuss how the MSC phenotype can influence the cargo and thus the regenerative potential of EVs. Induced pluripotent stem cell-derived mesenchymal progenitor cells (iMPs) may overcome current limitations of MSCs, and iMP-derived EVs are discussed as an alternative strategy. In the last part of the article, we focus on therapeutic applications of EVs and discuss both practical considerations for EV production and the current state of EV-based therapies

Clinical potential of mesenchymal stem cell-derived exosomes in bone regeneration

Bone metabolism is regulated by osteoblasts, osteoclasts, osteocytes, and stem cells. Pathologies such as osteoporosis, osteoarthritis, osteonecrosis, and traumatic fractures require effective treatments that favor bone formation and regeneration. Among these, cell therapy based on mesenchymal stem cells (MSC) has been proposed. MSC are osteoprogenitors, but their regenerative activity depends in part on their paracrine properties. These are mainly mediated by extracellular vesicle (EV) secretion. EV modulates regenerative processes such as inflammation, angiogenesis, cell proliferation, migration, and differentiation. Thus, MSC-EV are currently an important tool for the development of cell-free therapies in regenerative medicine. This review describes the current knowledge of the effects of MSC-EV in the different phases of bone regeneration. MSC-EV has been used by intravenous injection, directly or in combination with different types of biomaterials, in preclinical models of bone diseases. They have shown great clinical potential in regenerative medicine applied to bone. These findings should be confirmed through standardization of protocols, a better understanding of the mechanisms of action, and appropriate clinical trials. All that will allow the translation of such cell-free therapy to human clinic applications

Mesenchymal stromal cells-exosomes: a promising cell-free therapeutic tool for wound healing and cutaneous regeneration

Cutaneous regeneration at the wound site involves several intricate and dynamic processes which require a series of coordinated interactions implicating various cell types, growth factors, extracellular matrix (ECM), nerves, and blood vessels. Mesenchymal stromal cells (MSCs) take part in all the skin wound healing stages playing active and beneficial roles in animal models and humans. Exosomes, which are among the key products MSCs release, mimic the effects of parental MSCs. They can shuttle various effector proteins, messenger RNA (mRNA) and microRNAs (miRNAs) to modulate the activity of recipient cells, playing important roles in wound healing. Moreover, using exosomes avoids many risks associated with cell transplantation. Therefore, as a novel type of cell-free therapy, MSC-exosome -mediated administration may be safer and more efficient than whole cell. In this review, we provide a comprehensive understanding of the latest studies and observations on the role of MSC-exosome therapy in wound healing and cutaneous regeneration. In addition, we address the hypothesis of MSCs microenvironment extracellular vesicles (MSCs-MEVs) or MSCs microenvironment exosomes (MSCs-MExos) that need to take stock of and solved urgently in the related research about MSC-exosomes therapeutic applications. This review can inspire investigators to explore new research directions of MSC-exosome therapy in cutaneous repair and regeneration

Therapeutic Strategies of Secretome of Mesenchymal Stem Cell

Great progress has been made in the therapeutic strategies of multiple diseases that lack curative treatments with the transplantation of mesenchymal stem cells (MSC), such as in onco-hematological diseases, myocardial infarction (MI), cerebrovascular diseases, degenerative diseases of the nervous system (multiple sclerosis, Alzheimer’s disease), and diseases of the immune system, among others. Stem cells (SC) participate in the biological processes of tissue regeneration and repair through cell replication. Recently, the beneficial therapeutic effects of SCs that are generated by the release of proteins with paracrine actions and not by cell differentiation are more well known, and 80% of the therapeutic effect of SC is attributed to paracrine actions. The MSCs release large amounts of proteins and growth factors (GF), nucleic acids, proteasomes, exosomes, and microRNA, and membrane vesicles known as the secretome are released into the extracellular space, regulating multiple biological processes. Currently, the therapeutic strategies in tissue engineering (TE) and regenerative medicine (RM) are focused on the management of products derived from cells that act, both locally and remotely, in the affected tissue or organ, achieving regenerative actions. The application of new knowledge of the secretome initiates a change in the paradigm of regenerative therapy by knowing more about and using cell products derived from cells as a “factory” for biological drugs

Potential Therapeutic Applications of Exosomes in Bone Regenerative Medicine

The ability of bone regeneration is relatively robust, which is crucial for fracture healing, but delayed healing and nonunion are still common problems in clinical practice. Fortunately, exciting results have been achieved for regenerative medicine in recent years, especially in the area of stem cell-based treatment, but all these cell-based approaches face challenging problems, including immune rejection. For this reason, exosomes, stem cell-derived small vesicles of endocytic origin, have attracted the attention of many investigators in the field of bone regeneration. One of the attractive features of exosomes is that they are small and can travel between cells and deliver bioactive products, including miRNA, mRNA, proteins, and various other factors, to promote bone regeneration, with undetectable immune rejection. In this chapter, we intend to briefly update the recent progressions, and discuss the potential challenges in the target areas. Hopefully, our discussion would be helpful not only for the clinicians and the researchers in the specific disciplines but also for the general audiences as well

Cellular interactions in the tumor microenvironment: the role of secretome

Over the past years, it has become evident that cancer initiation and progression depends on several components of the tumor microenvironment, including inflammatory and immune cells, fibroblasts, endothelial cells, adipocytes, and extracellular matrix. These components of the tumor microenvironment and the neoplastic cells interact with each other providing pro and antitumor signals. The tumor-stroma communication occurs directly between cells or via a variety of molecules secreted, such as growth factors, cytokines, chemokines and microRNAs. This secretome, which derives not only from tumor cells but also from cancer-associated stromal cells, is an important source of key regulators of the tumorigenic process. Their screening and characterization could provide useful biomarkers to improve cancer diagnosis, prognosis, and monitoring of treatment responses.Agência financiadora Fundação de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) FAPESP 10/51168-0 12/06048-2 13/03839-1 National Council for Scientific and Technological Development (CNPq) CNPq 306216/2010-8 Fundacao para a Ciencia e a Tecnologia (FCT) UID/BIM/04773/2013 CBMR 1334info:eu-repo/semantics/publishedVersio