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

Ionic Liquid Composite Polybenzimidazol Membranes for High Temperature PEMFC Applications

A series of proton exchange membranes based on polybenzimidazole (PBI) were prepared using the low cost ionic liquids (ILs) derived from 1-butyl-3-methylimidazolium (BMIM) bearing different anions as conductive fillers in the polymeric matrix with the aim of enhancing the proton conductivity of PBI membranes. The composite membranes prepared by casting method (containing 5 wt. % of IL) exhibited good thermal, dimensional, mechanical, and oxidative stability for fuel cell applications. The effects of anion, temperature on the proton conductivity of phosphoric acid-doped membranes were systematically investigated by electrochemical impedance spectroscopy. The PBI composite membranes containing 1-butyl-3-methylimidazolium-derived ionic liquids exhibited high proton conductivity of 0.098 S·cm-1 at 120 ºC when tetrafluoroborate anion was present in the polymeric matrix. This conductivity enhancement might be attributed to the formed hydrogen-bond networks between the IL molecules and the phosphoric acid molecules distributed along the polymeric matrix

Proton conductivity through polybenzimidazole composite membranes containing silica nanofiber mats

The quest for sustainable and more efficient energy-converting devices has been the focus of researchers′ efforts in the past decades. In this study, SiO2 nanofiber mats were fabricated through an electrospinning process and later functionalized using silane chemistry to introduce different polar groups -OH (neutral), -SO3H (acidic) and -NH2 (basic). The modified nanofiber mats were embedded in PBI to fabricate mixed matrix membranes. The incorporation of these nanofiber mats in the PBI matrix showed an improvement in the chemical and thermal stability of the composite membranes. Proton conduction measurements show that PBI composite membranes containing nanofiber mats with basic groups showed higher proton conductivities, reaching values as high as 4 mS·cm−1 at 200 ºC

Ionic Liquid Composite Polybenzimidazol Membranes for High Temperature PEMFC Applications

[EN] A series of proton exchange membranes based on polybenzimidazole (PBI) were prepared using the low cost ionic liquids (ILs) derived from 1-butyl-3-methylimidazolium (BMIM) bearing different anions as conductive fillers in the polymeric matrix with the aim of enhancing the proton conductivity of PBI membranes. The composite membranes prepared by casting method (containing 5 wt. % of IL) exhibited good thermal, dimensional, mechanical, and oxidative stability for fuel cell applications. The effects of anion, temperature on the proton conductivity of phosphoric acid-doped membranes were systematically investigated by electrochemical impedance spectroscopy. The PBI composite membranes containing 1-butyl-3-methylimidazolium-derived ionic liquids exhibited high proton conductivity of 0.098 Scm(-1) at 120 degrees C when tetrafluoroborate anion was present in the polymeric matrix. This conductivity enhancement might be attributed to the formed hydrogen-bond networks between the IL molecules and the phosphoric acid molecules distributed along the polymeric matrix.The authors acknowledge the Spanish Ministerio de Economia y Competitividad (MINECO) for the financial support under the project ENE/2015-69203-R.Escorihuela, J.; Garcia Bernabe, A.; Montero Reguera, ÁE.; Sahuquillo, O.; Giménez Torres, E.; Compañ Moreno, V. (2019). Ionic Liquid Composite Polybenzimidazol Membranes for High Temperature PEMFC Applications. Polymers. 11(4):1-14. https://doi.org/10.3390/polym1104073211411

Proton Conductivity through Polybenzimidazole Composite Membranes Containing Silica Nanofiber Mats

[EN] The quest for sustainable and more efficient energy-converting devices has been the focus of researchers 0 efforts in the past decades. In this study, SiO2 nanofiber mats were fabricated through an electrospinning process and later functionalized using silane chemistry to introduce different polar groups OH (neutral), SO3H (acidic) and NH2 (basic). The modified nanofiber mats were embedded in PBI to fabricate mixed matrix membranes. The incorporation of these nanofiber mats in the PBI matrix showed an improvement in the chemical and thermal stability of the composite membranes. Proton conduction measurements show that PBI composite membranes containing nanofiber mats with basic groups showed higher proton conductivities, reaching values as high as 4 mS.cm(-1) at 200 degrees C.This research was funded by the Spanish Ministerio de Economia y Competitividad (MINECO) for the financial support, grant number ENE/2015-69203-R.Escorihuela, J.; Garcia Bernabe, A.; Montero Reguera, ÁE.; Andrio, A.; Sahuquillo, O.; Giménez Torres, E.; Compañ Moreno, V. (2019). Proton Conductivity through Polybenzimidazole Composite Membranes Containing Silica Nanofiber Mats. Polymers. 11(7):1-16. https://doi.org/10.3390/polym1107118211611

Polymer-modified sulfonated PEEK ionomer membranes and the use of Ru3Pd6Pt as cathode catalyst for H2/O2 fuel cells

[EN] Nanocomposite membranes incorporating electrospun nanofibers of SPEEK, blended with 30 wt% PVB within a water-based matrix of SPEEK with 35 wt% PVA using water as solvent, were prepared and characterized for their application as Polymer Electrolyte Membrane Fuel Cells (PEMFCs) in H-2/O-2 operating at low temperatures. Compared with a dense bulk phase, an improvement of proton conductivity in the SPEEK-30PVB nanofiber framework was observed. The incorporation of the SPEEK-30PVB nanofibers provides mechanical improvement while the matrix phase of SPEEK-35PVA emphasizes the proton conductivity at crosslinking temperatures up to 140 degrees C. PEMFC performance tests showed promising results for the use of these novel low cost membranes. The nanocomposite membrane reached a power density which is 25% higher than that of Nafion117 membranes with MEAs constructed with Pt loading in anode and in cathode. However, when the Pt of the cathode is substituted by Ru3Pd6Pt, the power density is lower in Nafion117 MEAs than in the nanocomposite. When used commercial Pt-carbon cloth (Pt-ETEK) for the electrodes, the power density achieved is 1.4 times higher for the Nafion117 MEAs than SPEEK nano-composites. The differences observed in performance is attributed to the large polarization losses found in the composite membranes because of the interfacial phenomena associated with the use of commercial Nafion-based electrodes.This research is in the frame of Support Programme for Research and Development of the Polytechnic University of Valencia, and the Ministry of Science and for funding provided through the projects: ENE2015-69203-R. OSF thanks to CONACYT-Mexico for supporting this research with the grant 475920.Martínez-Casillas, D.; Solorza, O.; Mollá Romano, S.; Montero Reguera, ÁE.; Garcia Bernabe, A.; Compañ Moreno, V. (2019). Polymer-modified sulfonated PEEK ionomer membranes and the use of Ru3Pd6Pt as cathode catalyst for H2/O2 fuel cells. International Journal of Hydrogen Energy. 44(1):295-303. https://doi.org/10.1016/j.ijhydene.2018.09.217S29530344