Manufacturing of human extracellular vesicle-based therapeutics for clinical use

International Journal of Molecular Sciences

Volumn 18, Issue 6, 2017, Pages

  Gimona, Mario ^a   Pachler, Karin ^a   Laner Plamberger, Sandra ^a   Schallmoser, Katharina ^a   Rohde, Eva ^a  

^a PARACELSUS MEDICAL UNIVERSITY   (Austria)

Author keywords

Critical size bone defect; Epidermolysis bullosa; Exosomes; Extracellular vesicles; Good manufacturing practice; Mesenchymal stromal cells; Spinal cord injury; Therapeutics; Vesicular secretome fraction

Indexed keywords

COLLAGEN TYPE 7; CONNECTIVE TISSUE GROWTH FACTOR; DRUG CARRIER; MESSENGER RNA; MICRORNA; WNT4 PROTEIN; BIOLOGICAL PRODUCT;

AFFINITY CHROMATOGRAPHY; ANGIOGENESIS; ANION EXCHANGE CHROMATOGRAPHY; ARTICLE; BIOLOGICAL ACTIVITY; BONE REGENERATION; CYTOTOXICITY; DIAFILTRATION; DISTRACTION OSTEOGENESIS; DRUG BIOAVAILABILITY; DRUG MANUFACTURE; DRUG PURIFICATION; DRUG STABILITY; ELECTRON MICROSCOPY; EPIDERMOLYSIS BULLOSA DYSTROPHICA; EXOSOME; GENE SILENCING; GLIOBLASTOMA; HUMAN; IMMUNOMODULATION; LUNG CARCINOMA; MESENCHYMAL STROMA CELL; NEUROPROTECTION; OSTEOGENESIS IMPERFECTA; PRACTICE GUIDELINE; SIZE EXCLUSION CHROMATOGRAPHY; SPINAL CORD INJURY; THROMBOCYTE RICH PLASMA; WOUND HEALING; ANIMAL; CELL FRACTIONATION; ISOLATION AND PURIFICATION; MEMBRANE MICROPARTICLE; PROCEDURES; STANDARDS;

ANIMALS; BIOLOGICAL PRODUCTS; CELL FRACTIONATION; CELL-DERIVED MICROPARTICLES; EXOSOMES; EXTRACELLULAR VESICLES; HUMANS;

EID: 85020416976     PISSN: 16616596     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms18061190     Document Type: Article

References (93)

1. Gyorgy, B., Szabo, T.G., Pasztoi, M., Pal, Z., Misjak, P., Aradi, B., Laszlo, V., Pallinger, E., Pap, E., Kittel, A., et al. Membrane vesicles, current state-of-the-art: Emerging role of extracellular vesicles. Cell. Mol. Life Sci. 2011, 68, 2667-2688.
2. Zitvogel, L., Regnault, A., Lozier, A., Wolfers, J., Flament, C., Tenza, D., Ricciardi-Castagnoli, P., Raposo, G., Amigorena, S. Eradication of established murine tumors using a novel cell-free vaccine: Dendritic cell-derived exosomes. Nat. Med. 1998, 4, 594-600.
3. Lamparski, H.G., Metha-Damani, A., Yao, J.Y., Patel, S., Hsu, D.H., Ruegg, C., Le Pecq, J.B. Production and characterization of clinical grade exosomes derived from dendritic cells. J. Immunol. Methods 2002, 270, 211-226.
4. Escudier, B., Dorval, T., Chaput, N., Andre, F., Caby, M.P., Novault, S., Flament, C., Leboulaire, C., Borg, C., Amigorena, S., et al. Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: Results of thefirst phase I clinical trial. J. Transl. Med. 2005, 3, 10.
5. Morse, M.A., Garst, J., Osada, T., Khan, S., Hobeika, A., Clay, T.M., Valente, N., Shreeniwas, R., Sutton, M.A., Delcayre, A., et al. A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer. J. Transl. Med. 2005, 3, 9.
6. Besse, B., Charrier, M., Lapierre, V., Dansin, E., Lantz, O., Planchard, D., Le Chevalier, T., Livartoski, A., Barlesi, F., Laplanche, A., et al. Dendritic cell-derived exosomes as maintenance immunotherapy after first line chemotherapy in NSCLC. Oncoimmunology 2016, 5, e1071008.
7. Lener, T., Gimona, M., Aigner, L., Borger, V., Buzas, E., Camussi, G., Chaput, N., Chatterjee, D., Court, F.A., Del Portillo, H.A., et al. Applying extracellular vesicles based therapeutics in clinical trials-An ISEV position paper. J. Extracell. Vesicles 2015, 4, 30087.
8. Riazifar, M., Pone, E.J., Lotvall, J., Zhao, W. Stem Cell Extracellular Vesicles: Extended Messages of Regeneration. Annu. Rev. Pharmacol. Toxicol. 2017, 57, 125-154.
9. Lai, R.C., Arslan, F., Lee, M.M., Sze, N.S., Choo, A., Chen, T.S., Salto-Tellez, M., Timmers, L., Lee, C.N., El Oakley, R.M., et al. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res. 2010, 4, 214-222.
10. Chen, T.S., Arslan, F., Yin, Y., Tan, S.S., Lai, R.C., Choo, A.B., Padmanabhan, J., Lee, C.N., de Kleijn, D.P., Lim, S.K. Enabling a robust scalable manufacturing process for therapeutic exosomes through oncogenic immortalization of human ESC-derived MSCs. J. Transl. Med. 2011, 9, 47.
11. Tan, S.S., Yin, Y., Lee, T., Lai, R.C., Yeo, R.W., Zhang, B., Choo, A., Lim, S.K. Therapeutic MSC exosomes are derived from lipid raft microdomains in the plasma membrane. J. Extracell. Vesicles 2013.
12. EL Andaloussi, S., Mager, I., Breakefield, X.O., Wood, M.J. Extracellular vesicles: Biology and emerging therapeutic opportunities. Nat. Rev. Drug Discov. 2013, 12, 347-357.
13. Zhang, B., Yin, Y., Lai, R.C., Tan, S.S., Choo, A.B., Lim, S.K. Mesenchymal stem cells secrete immunologically active exosomes. Stem Cells Dev. 2014, 23, 1233-1244.
14. Akyurekli, C., Le, Y., Richardson, R.B., Fergusson, D., Tay, J., Allan, D.S. A systematic review of preclinical studies on the therapeutic potential of mesenchymal stromal cell-derived microvesicles. Stem Cell Rev. 2015, 11, 150-160.
15. Lamichhane, T.N., Sokic, S., Schardt, J.S., Raiker, R.S., Lin, J.W., Jay, S.M. Emerging roles for extracellular vesicles in tissue engineering and regenerative medicine. Tissue Eng. Part B Rev. 2015, 21, 45-54.
16. Heldring, N., Mager, I., Wood, M.J., Le Blanc, K., Andaloussi, S.E. Therapeutic Potential of Multipotent Mesenchymal Stromal Cells and Their Extracellular Vesicles. Hum. Gene Ther. 2015, 26, 506-517.
17. Rani, S., Ryan, A.E., Griffin, M.D., Ritter, T. Mesenchymal Stem Cell-derived Extracellular Vesicles: Toward Cell-Free Therapeutic Applications. Mol. Ther. 2015, 23, 812-823.
18. Zhang, B., Shen, L., Shi, H., Pan, Z., Wu, L., Yan, Y., Zhang, X., Mao, F., Qian, H., Xu, W. Exosomes from Human Umbilical Cord Mesenchymal Stem Cells: Identification, Purification, and Biological Characteristics. Stem Cells Int. 2016, 2016, 1929536.
19. Fais, S., O’Driscoll, L., Borras, F.E., Buzas, E., Camussi, G., Cappello, F., Carvalho, J., Cordeiro da Silva, A., Del Portillo, H., El Andaloussi, S., et al. Evidence-Based Clinical Use of Nanoscale Extracellular Vesicles in Nanomedicine. ACS Nano 2016, 10, 3886-3899.
20. Beer, L., Mildner, M., Gyongyosi, M., Ankersmit, H.J. Peripheral blood mononuclear cell secretome for tissue repair. Apoptosis 2016, 21, 1336-1353.
21. Ragni, E., Banfi, F., Barilani, M., Cherubini, A., Parazzi, V., Larghi, P., Dolo, V., Bollati, V., Lazzari, L. Extracellular Vesicle-Shuttled mRNA in Mesenchymal Stem Cell Communication. Stem Cells 2017, 35, 1093-1105.
22. Jiang, L., Vader, P., Schiffelers, R.M. Extracellular vesicles for nucleic acid delivery: Progress and prospects for safe RNA-based gene therapy. Gene Ther. 2017, 24, 157-166.
23. Phinney, D.G., Pittenger, M.F. Concise Review: MSC-Derived Exosomes for Cell-Free Therapy. Stem Cells 2017, 35, 851-858.
24. Bailey, A.M., Mendicino, M., Au, P. An FDA perspective on preclinical development of cell-based regenerative medicine products. Nat. Biotechnol. 2014, 32, 721-723.
25. Horwitz, E.M., Prockop, D.J., Fitzpatrick, L.A., Koo, W.W., Gordon, P.L., Neel, M., Sussman, M., Orchard, P., Marx, J.C., Pyeritz, R.E., et al. Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat. Med. 1999, 5, 309-313.
26. Kitoh, H., Kitakoji, T., Tsuchiya, H., Mitsuyama, H., Nakamura, H., Katoh, M., Ishiguro, N. Transplantation of marrow-derived mesenchymal stem cells and platelet-rich plasma during distraction osteogenesis—A preliminary result of three cases. Bone 2004, 35, 892-898.
27. Yamada, Y., Ueda, M., Hibi, H., Nagasaka, T. Translational research for injectable tissue-engineered bone regeneration using mesenchymal stem cells and platelet-rich plasma: From basic research to clinical case study. Cell Transplant. 2004, 13, 343-355.
28. Yamada, Y., Ueda, M., Naiki, T., Takahashi, M., Hata, K., Nagasaka, T. Autogenous injectable bone for regeneration with mesenchymal stem cells and platelet-rich plasma: Tissue-engineered bone regeneration. Tissue Eng. 2004, 10, 955-964.
29. Ito, K., Yamada, Y., Nagasaka, T., Baba, S., Ueda, M. Osteogenic potential of injectable tissue-engineered bone: A comparison among autogenous bone, bone substitute (Bio-oss), platelet-rich plasma, and tissue-engineered bone with respect to their mechanical properties and histological findings. J. Biomed. Mater. Res. A 2005, 73, 63-72.
30. Qi, Y., Niu, L., Zhao, T., Shi, Z., Di, T., Feng, G., Li, J., Huang, Z. Combining mesenchymal stem cell sheets with platelet-rich plasma gel/calcium phosphate particles: A novel strategy to promote bone regeneration. Stem Cell Res. Ther. 2015, 6, 256.
31. Toben, D., Schroeder, I., El Khassawna, T., Mehta, M., Hoffmann, J.E., Frisch, J.T., Schell, H., Lienau, J., Serra, A., Radbruch, A., et al. Fracture healing is accelerated in the absence of the adaptive immune system. J. Bone Miner. Res. 2011, 26, 113-124.
32. Mountziaris, P.M., Spicer, P.P., Kasper, F.K., Mikos, A.G. Harnessing and modulating inflammation in strategies for bone regeneration. Tissue Eng. Part B Rev. 2011, 17, 393-402.
33. Schlundt, C., Schell, H., Goodman, S.B., Vunjak-Novakovic, G., Duda, G.N., Schmidt-Bleek, K. Immune modulation as a therapeutic strategy in bone regeneration. J. Exp. Orthop. 2015, 2, 1.
34. Blazquez, R., Sanchez-Margallo, F.M., de la Rosa, O., Dalemans, W., Alvarez, V., Tarazona, R., Casado, J.G. Immunomodulatory Potential of Human Adipose Mesenchymal Stem Cells Derived Exosomes on in vitro Stimulated T Cells. Front. Immunol. 2014, 5, 556.
35. Chen, W., Huang, Y., Han, J., Yu, L., Li, Y., Lu, Z., Li, H., Liu, Z., Shi, C., Duan, F., et al. Immunomodulatory effects of mesenchymal stromal cells-derived exosome. Immunol. Res. 2016, 64, 831-840.
36. Di Trapani, M., Bassi, G., Midolo, M., Gatti, A., Kamga, P.T., Cassaro, A., Carusone, R., Adamo, A., Krampera, M. Differential and transferable modulatory effects of mesenchymal stromal cell-derived extracellular vesicles on T, B and NK cell functions. Sci. Rep. 2016, 6, 24120.
37. Cui, Y., Luan, J., Li, H., Zhou, X., Han, J. Exosomes derived from mineralizing osteoblasts promote ST2 cell osteogenic differentiation by alteration of microRNA expression. FEBS Lett. 2016, 590, 185-192.
38. Qin, Y., Wang, L., Gao, Z., Chen, G., Zhang, C. Bone marrow stromal/stem cell-derived extracellular vesicles regulate osteoblast activity and differentiation in vitro and promote bone regeneration in vivo. Sci. Rep. 2016, 6, 21961.
39. Zhang, S., Chu, W.C., Lai, R.C., Lim, S.K., Hui, J.H., Toh, W.S. Exosomes derived from human embryonic mesenchymal stem cells promote osteochondral regeneration. Osteoarthr. Cartil. 2016, 24, 2135-2140.
40. Liu, X., Li, Q., Niu, X., Hu, B., Chen, S., Song, W., Ding, J., Zhang, C., Wang, Y. Exosomes Secreted from Human-Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Prevent Osteonecrosis of the Femoral Head by Promoting Angiogenesis. Int. J. Biol. Sci. 2017, 13, 232-244.
41. 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.
42. Fine, J.D., Bruckner-Tuderman, L., Eady, R.A., Bauer, E.A., Bauer, J.W., Has, C., Heagerty, A., Hintner, H., Hovnanian, A., Jonkman, M.F., et al. Inherited epidermolysis bullosa: Updated recommendations on diagnosis and classification. J. Am. Acad. Dermatol. 2014, 70, 1103-1126.
43. Fine, J.D., Mellerio, J.E. Extracutaneous manifestations and complications of inherited epidermolysis bullosa: Part II. Other organs. J. Am. Acad. Dermatol. 2009, 61, 387-402.
44. Petrof, G., Lwin, S.M., Martinez-Queipo, M., Abdul-Wahab, A., Tso, S., Mellerio, J.E., Slaper-Cortenbach, I., Boelens, J.J., Tolar, J., Veys, P., et al. Potential of Systemic Allogeneic Mesenchymal Stromal Cell Therapy for Children with Recessive Dystrophic Epidermolysis Bullosa. J. Investig. Dermatol. 2015, 135, 2319-2321.
45. Zhang, B., Wang, M., Gong, A., Zhang, X., Wu, X., Zhu, Y., Shi, H., Wu, L., Zhu, W., Qian, H., et al. HucMSC-Exosome Mediated-Wnt4 Signaling Is Required for CutaneousWound Healing. Stem Cells 2015, 33, 2158-2168.
46. Zhang, B., Shi, Y., Gong, A., Pan, Z., Shi, H., Yang, H., Fu, H., Yan, Y., Zhang, X., Wang, M., et al. HucMSC Exosome-Delivered 14-3-3ξ Orchestrates Self-Control of the Wnt Response via Modulation of YAP During Cutaneous Regeneration. Stem Cells 2016, 34, 2485-2500.
47. Hu, L., Wang, J., Zhou, X., Xiong, Z., Zhao, J., Yu, R., Huang, F., Zhang, H., Chen, L. Exosomes derived from human adipose mensenchymal stem cells accelerates cutaneous wound healing via optimizing the characteristics of fibroblasts. Sci. Rep. 2016, 6, 32993.
48. Williams, P.R., Marincu, B.N., Sorbara, C.D., Mahler, C.F., Schumacher, A.M., Griesbeck, O., Kerschensteiner, M., Misgeld, T. A recoverable state of axon injury persists for hours after spinal cord contusion in vivo. Nat. Commun. 2014, 5, 5683.
49. Yu, Y.M., Gibbs, K.M., Davila, J., Campbell, N., Sung, S., Todorova, T.I., Otsuka, S., Sabaawy, H.E., Hart, R.P., Schachner, M. MicroRNA miR-133b is essential for functional recovery after spinal cord injury in adult zebrafish. Eur. J. Neurosci. 2011, 33, 1587-1597.
50. Xin, H., Li, Y., Buller, B., Katakowski, M., Zhang, Y., Wang, X., Shang, X., Zhang, Z.G., Chopp, M. Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem Cells 2012, 30, 1556-1564.
51. Xin, H., Li, Y., Liu, Z., Wang, X., Shang, X., Cui, Y., Zhang, Z.G., Chopp, M. miR-133b promotes neural plasticity and functional recovery after treatment of stroke with multipotent mesenchymal stromal cells in rats via transfer of exosome-enriched extracellular particles. Stem Cells 2013, 31, 2737-2746.
52. Neirinckx, V., Agirman, G., Coste, C., Marquet, A., Dion, V., Rogister, B., Franzen, R., Wislet, S. Adult bone marrow mesenchymal and neural crest stem cells are chemoattractive and accelerate motor recovery in a mouse model of spinal cord injury. Stem Cell Res. Ther. 2015, 6, 211.
53. Doeppner, T.R., Herz, J., Gorgens, A., Schlechter, J., Ludwig, A.K., Radtke, S., de Miroschedji, K., Horn, P.A., Giebel, B., Hermann, D.M. Extracellular Vesicles Improve Post-Stroke Neuroregeneration and Prevent Postischemic Immunosuppression. Stem Cells Transl. Med. 2015, 4, 1131-1143.
54. De Rivero Vaccari, J.P., Brand, F., III, Adamczak, S., Lee, S.W., Perez-Barcena, J., Wang, M.Y., Bullock, M.R., Dietrich, W.D., Keane, R.W. Exosome-mediated inflammasome signaling after central nervous system injury. J. Neurochem. 2016, 136 (Suppl. 1), 39-48.
55. Han, D., Wu, C., Xiong, Q., Zhou, L., Tian, Y. Anti-inflammatory Mechanism of Bone Marrow Mesenchymal Stem Cell Transplantation in Rat Model of Spinal Cord Injury. Cell Biochem. Biophys. 2015, 71, 1341-1347.
56. Teixeira, F.G., Carvalho, M.M., Neves-Carvalho, A., Panchalingam, K.M., Behie, L.A., Pinto, L., Sousa, N., Salgado, A.J. Secretome of mesenchymal progenitors from the umbilical cord acts as modulator of neural/glial proliferation and differentiation. Stem Cell Rev. 2015, 11, 288-297.
57. Teixeira, F.G., Carvalho, M.M., Panchalingam, K.M., Rodrigues, A.J., Mendes-Pinheiro, B., Anjo, S., Manadas, B., Behie, L.A., Sousa, N., Salgado, A.J. Impact of the Secretome of Human Mesenchymal Stem Cells on Brain Structure and Animal Behavior in a Rat Model of Parkinson’s Disease. Stem Cells Transl. Med. 2017, 6, 634-646.
58. Buzas, E.I., Gyorgy, B., Nagy, G., Falus, A., Gay, S. Emerging role of extracellular vesicles in inflammatory diseases. Nat. Rev. Rheumatol. 2014, 10, 356-364.
59. Tjalsma, H., Bolhuis, A., Jongbloed, J.D., Bron, S., van Dijl, J.M. Signal peptide-dependent protein transport in Bacillus subtilis: A genome-based survey of the secretome. Microbiol. Mol. Biol. Rev. 2000, 64, 515-547.
60. Haider, T., Hoftberger, R., Ruger, B., Mildner, M., Blumer, R., Mitterbauer, A., Buchacher, T., Sherif, C., Altmann, P., Redl, H., et al. The secretome of apoptotic human peripheral blood mononuclear cells attenuates secondary damage following spinal cord injury in rats. Exp. Neurol. 2015, 267, 230-242.
61. Cohn, E.J., Oncley, J.L., Strong, L.E., Hughes, W.L., Armstrong, S.H. Chemical, Clinical, and Immunological Studies on the Products of Human Plasma Fractionation. I. The Characterization of the Protein Fractions of Human Plasma. J. Clin. Investig. 1944, 23, 417-432.
62. Kowal, J., Arras, G., Colombo, M., Jouve, M., Morath, J.P., Primdal-Bengtson, B., Dingli, F., Loew, D., Tkach, M., Thery, C. Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proc. Natl. Acad. Sci. USA 2016, 113, E968-E977.
63. Lai, R.C., Tan, S.S., Yeo, R.W., Choo, A.B., Reiner, A.T., Su, Y., Shen, Y., Fu, Z., Alexander, L., Sze, S.K., et al. MSC secretes at least 3 EV types each with a unique permutation of membrane lipid, protein and RNA. J. Extracell. Vesicles 2016, 5, 29828.
64. Willms, E., Johansson, H.J., Mager, I., Lee, Y., Blomberg, K.E., Sadik, M., Alaarg, A., Smith, C.I., Lehtio, J., El Andaloussi, S., et al. Cells release subpopulations of exosomes with distinct molecular and biological properties. Sci. Rep. 2016, 6, 22519.
65. Tauro, B.J., Greening, D.W., Mathias, R.A., Mathivanan, S., Ji, H., Simpson, R.J. Two distinct populations of exosomes are released from LIM1863 colon carcinoma cell-derived organoids. Mol. Cell. Proteomics 2013, 12, 587-598.
66. Xu, R., Greening, D.W., Zhu, H.J., Takahashi, N., Simpson, R.J. Extracellular vesicle isolation and characterization: Toward clinical application. J. Clin. Investig. 2016, 126, 1152-1162.
67. Balaj, L., Atai, N.A., Chen, W., Mu, D., Tannous, B.A., Breakefield, X.O., Skog, J., Maguire, C.A. Heparin affinity purification of extracellular vesicles. Sci. Rep. 2015, 5, 10266.
68. + extracellular vesicles from mesenchymal stromal cells rescue cognitive impairments after TBI. Proc. Natl. Acad. Sci. USA 2016, 113, 170-175.
69. Long, Q., Upadhya, D., Hattiangady, B., Kim, D.K., An, S.Y., Shuai, B., Prockop, D.J., Shetty, A.K. Intranasal MSC-derived A1-exosomes ease inflammation, and prevent abnormal neurogenesis and memory dysfunction after status epilepticus. Proc. Natl. Acad. Sci. USA 2017, 114, E3536-E3545.
70. Gardiner, C., Di Vizio, D., Sahoo, S., Thery, C., Witwer, K.W., Wauben, M., Hill, A.F. Techniques used for the isolation and characterization of extracellular vesicles: Results of a worldwide survey. J. Extracell. Vesicles 2016, 5, 32945.
71. Heinemann, M.L., Ilmer, M., Silva, L.P., Hawke, D.H., Recio, A., Vorontsova, M.A., Alt, E., Vykoukal, J. Benchtop isolation and characterization of functional exosomes by sequential filtration. J. Chromatogr. A 2014, 1371, 125-135.
72. Gamez-Valero, A., Monguio-Tortajada, M., Carreras-Planella, L., Franquesa, M., Beyer, K., Borras, F.E. Size-Exclusion Chromatography-based isolation minimally alters Extracellular Vesicles’ characteristics compared to precipitating agents. Sci. Rep. 2016, 6, 33641.
73. Dominici, M., Le Blanc, K., Mueller, I., Slaper-Cortenbach, I., Marini, F., Krause, D., Deans, R., Keating, A., Prockop, D., Horwitz, E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006, 8, 315-317.
74. Chen, Y.S., Chen, Y.A., Tsai, P.H., Chen, C.P., Shaw, S.W., Hsuan, Y. Mesenchymal Stem Cell: Considerations for Manufacturing and Clinical Trials on Cell Therapy Product. Int. J. Stem Cell Res. Ther. 2016, 3, 29.
75. Camilleri, E.T., Gustafson, M.P., Dudakovic, A., Riester, S.M., Garces, C.G., Paradise, C.R., Takai, H., Karperien, M., Cool, S., Sampen, H.J., et al. Identification and validation of multiple cell surface markers of clinical-grade adipose-derived mesenchymal stromal cells as novel release criteria for good manufacturing practice-compliant production. Stem Cell Res. Ther. 2016, 7, 107.
76. Lee, R.H., Yu, J.M., Foskett, A.M., Peltier, G., Reneau, J.C., Bazhanov, N., Oh, J.Y., Prockop, D.J. TSG-6 as a biomarker to predict efficacy of human mesenchymal stem/progenitor cells (hMSCs) in modulating sterile inflammation in vivo. Proc. Natl. Acad. Sci. USA 2014, 111, 16766-16771.
77. Samsonraj, R.M., Rai, B., Sathiyanathan, P., Puan, K.J., Rotzschke, O., Hui, J.H., Raghunath, M., Stanton, L.W., Nurcombe, V., Cool, S.M. Establishing criteria for human mesenchymal stem cell potency. Stem Cells 2015, 33, 1878-1891.
78. Lotvall, J., Hill, A.F., Hochberg, F., Buzas, E.I., Di Vizio, D., Gardiner, C., Gho, Y.S., Kurochkin, I.V., Mathivanan, S., Quesenberry, P., et al. Minimal experimental requirements for definition of extracellular vesicles and their functions: A position statement from the International Society for Extracellular Vesicles. J. Extracell. Vesicles 2014, 3, 26913.
79. O’Loughlin, A.J., Mager, I., de Jong, O.G., Varela, M.A., Schiffelers, R.M., El Andaloussi, S., Wood, M.J., Vader, P. Functional Delivery of Lipid-Conjugated siRNA by Extracellular Vesicles. Mol. Ther. 2017.
80. Kim, M.S., Haney, M.J., Zhao, Y., Mahajan, V., Deygen, I., Klyachko, N.L., Inskoe, E., Piroyan, A., Sokolsky, M., Okolie, O., et al. Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells. Nanomed. Nanotechnol. Biol. Med. 2016, 12, 655-664.
81. Suzuki, E., Fujita, D., Takahashi, M., Oba, S., Nishimatsu, H. Stem cell-derived exosomes as a therapeutic tool for cardiovascular disease. World J. Stem Cells 2016, 8, 297-305.
82. Dai, S., Wei, D., Wu, Z., Zhou, X., Wei, X., Huang, H., Li, G. Phase I clinical trial of autologous ascites-derived exosomes combined with GM-CSF for colorectal cancer. Mol. Ther. 2008, 16, 782-790.
83. Di Rocco, G., Baldari, S., Toietta, G. Towards Therapeutic Delivery of Extracellular Vesicles: Strategies for In Vivo Tracking and Biodistribution Analysis. Stem Cells Int. 2016.
84. Wen, S.W., Sceneay, J., Lima, L.G., Wong, C.S., Becker, M., Krumeich, S., Lobb, R.J., Castillo, V., Wong, K.N., Ellis, S., et al. The Biodistribution and Immune Suppressive Effects of Breast Cancer-Derived Exosomes. Cancer Res. 2016, 76, 6816-6827.
85. Morishita, M., Takahashi, Y., Nishikawa, M., Takakura, Y. Pharmacokinetics of Exosomes-An Important Factor for Elucidating the Biological Roles of Exosomes and for the Development of Exosome-Based Therapeutics. J. Pharm. Sci. 2017.
86. Lai, C.P., Kim, E.Y., Badr, C.E., Weissleder, R., Mempel, T.R., Tannous, B.A., Breakefield, X.O. Visualization and tracking of tumour extracellular vesicle delivery and RNA translation using multiplexed reporters. Nat. Commun. 2015, 6, 7029.
87. Takahashi, Y., Nishikawa, M., Shinotsuka, H., Matsui, Y., Ohara, S., Imai, T., Takakura, Y. Visualization and in vivo tracking of the exosomes of murine melanoma B16-BL6 cells in mice after intravenous injection. J. Biotechnol. 2013, 165, 77-84.
88. Mateescu, B., Kowal, E.J., van Balkom, B.W., Bartel, S., Bhattacharyya, S.N., Buzas, E.I., Buck, A.H., de Candia, P., Chow, F.W., Das, S., et al. Obstacles and opportunities in the functional analysis of extracellular vesicle RNA—An ISEV position paper. J. Extracell. Vesicles 2017.
89. Lee, R.H., Pulin, A.A., Seo, M.J., Kota, D.J., Ylostalo, J., Larson, B.L., Semprun-Prieto, L., Delafontaine, P., Prockop, D.J. Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell 2009, 5, 54-63.
90. Kordelas, L., Rebmann, V., Ludwig, A.K., Radtke, S., Ruesing, J., Doeppner, T.R., Epple, M., Horn, P.A., Beelen, D.W., Giebel, B. MSC-derived exosomes: A novel tool to treat therapy-refractory graft-versus-host disease. Leukemia 2014, 28, 970-973.
91. Schuhmacher, A., Gassmann, O., Hinder, M. Changing RandD models in research-based pharmaceutical companies. J. Transl. Med. 2016, 14, 105. [PubMed]
92. O’Brien, T., Creane, M., Windebank, A.J., Terzic, A., Dietz, A.B. Translating stem cell research to the clinic: A primer on translational considerations for your first stem cell protocol. Stem Cell Res. Ther. 2015, 6, 146.
93. Ramsey, B.W., Nepom, G.T., Lonial, S. Academic, Foundation, and Industry Collaboration in Finding New Therapies. N. Engl. J. Med. 2017, 376, 1762-1769.