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Biochemistry (Moscow)

, Volume 84, Issue 11, pp 1375–1389 | Cite as

Conditioned Medium of Mesenchymal Stromal Cells: A New Class of Therapeutics

  • N. V. BogatchevaEmail author
  • M. E. Coleman
Review
  • 47 Downloads

Abstract

Mesenchymal stromal cell (MSCs) represent a class of biologics with the prospects for employment as immunomodulatory, tissue-protective, and regenerative therapeutics. In parallel with cellular therapy, cell-free therapy based on MSC-secreted bioactive factors is being actively developed. MSCs secrete a variety of protein, peptide, RNA, and lipid mediators which can be concentrated, frozen, or even lyophilized without loss of activity, which gives them a certain advantage over cellular products requiring liquid nitrogen storage and infrastructure to revive frozen cells. This review (i) describes currently conducted clinical trials of cell-free products containing MSC secretome; (ii) summarizes main approaches to the generation and characterization of conditioned media concentrates and extracellular vesicle isolates; (iii) analyzes a variety of preclinical studies where effectiveness of secretome products has been shown; and (iv) summarizes current knowledge about secretome bioactive components obtained by analysis of in vivo models testing the therapeutic potential of the MSC secretome.

Keywords

MSC secretome conditioned media extracellular vesicles exosomes 

Abbriviation

BM-MSCs, ASCs, DP-MCSs, and UC-MSCs

mesenchymal stromal cells isolated from bone marrow, adipose tissue, dental pulp, and umbilical cord

CM

conditioned medium

EV

extracellular vesicles

GMP

Good Manufacturing Practices

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Notes

Funding

This work was partially supported by the National Institute of Diabetes, Digestive and Kidney Diseases (R41 1R41DK115317 grant to Dr. Coleman).

References

  1. 1.
    Squillaro, T., Peluso, G., and Galderisi, U. (2016) Clinical trials with mesenchymal stem cells: an update, Cell Transplant., 25, 829–848, doi:  https://doi.org/10.3727/096368915x689622.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Galipeau, J., and Sensebe, L. (2018) Mesenchymal stromal cells: clinical challenges and therapeutic opportunities, Cell Stem Cell, 22, 824–833, doi:  https://doi.org/10.1016/j.stem.2018.05.004.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Olsen, T. R., Ng, K. S., Lock, L. T., Ahsan, T., and Rowley, J. A. (2018) Peak MSC — are we there yet? Front. Med., 5, 178, doi:  https://doi.org/10.3389/fmed.2018.00178.CrossRefGoogle Scholar
  4. 4.
    Kuzmina, L. A., Petinati, N. A., Parovichnikova, E. N., Lubimova, L. S., Gribanova, E. O., Gaponova, T. V., Shipounova, I. N., Zhironkina, O. A., Bigildeev, A. E., Svinareva, D. A., Drize, N. J., and Savchenko, V. G. (2012) Multipotent mesenchymal stromal cells for the prophylaxis of acute graft-versus-host disease — A phase II study, Stem Cells Int., 2012, 968213, doi:  https://doi.org/10.1155/2012/968213.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Kuzmina, L. A., Petinati, N. A., Shipounova, I. N., Sats, N. V., Bigildeev, A. E., Zezina, E. A., Popova, M. D., Drize, N. J., Parovichnikova, E. N., and Savchenko, V. G. (2016) Analysis of multipotent mesenchymal stromal cells used for acute graft-versus-host disease prophylaxis, Eur. J. Haematol., 96, 425–434, doi:  https://doi.org/10.1111/ejh.12613.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Kuzmina, L. A., Petinati, N. A., Sats, N. V., Drize, N. J., Risinskaya, N. V., Sudarikov, A. B., Vasilieva, V. A., Drokov, M. Y., Michalzova, E. D., Parovichnikova, E. N., and Savchenko, V. G. (2016) Long-term survival of donor bone marrow multipotent mesenchymal stromal cells implanted into the periosteum of patients with allogeneic graft failure, Int. J. Hematol., 104, 403–407, doi:  https://doi.org/10.1007/s12185-016-2014-2.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Petinati, N., Drize, N., Sats, N., Risinskaya, N., Sudarikov, A., Drokov, M., Dubniak, D., Kraizman, A., Nareyko, M., Popova, N., Firsova, M., Kuzmina, L., Parovichnikova, E., and Savchenko, V. (2018) Recovery of donor hematopoiesis after graft failure and second hematopoietic stem cell trans-plantation with intraosseous administration of mesenchymal stromal cells, Stem Cells Int., 2018, 6495018, doi:  https://doi.org/10.1155/2018/6495018.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Caplan, A. I. (2017) Mesenchymal stem cells: time to change the name! Stem Cells Transl. Med., 6, 1445–1451, doi:  https://doi.org/10.1002/sctm.17-0051.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Gnecchi, M., Zhang, Z., Ni, A., and Dzau, V. J. (2008) Paracrine mechanisms in adult stem cell signaling and therapy, Circ. Res., 103, 1204–1219, doi:  https://doi.org/10.1161/circresaha.108.176826.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Rehman, J., Traktuev, D., Li, J., Merfeld-Clauss, S., Temm-Grove, C. J., Bovenkerk, J. E., Pell, C. L., Johnstone, B. H., Considine, R. V., and March, K. L. (2004) Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells, Circulation, 109, 1292–1298, doi:  https://doi.org/10.1161/01.CIR.0000121425.42966.F1.PubMedCrossRefGoogle Scholar
  11. 11.
    Chang, M. G., Tung, L., Sekar, R. B., Chang, C. Y., Cysyk, J., Dong, P., Marban, E., and Abraham, M. R. (2006) Proarrhythmic potential of mesenchymal stem cell transplantation revealed in an in vitro coculture model, Circulation, 113, 1832–1841, doi:  https://doi.org/10.1161/circulationa-ha.105.593038.PubMedCrossRefGoogle Scholar
  12. 12.
    Breitbach, M., Bostani, T., Roell, W., Xia, Y., Dewald, O., Nygren, J. M., Fries, J. W., Tiemann, K., Bohlen, H., Hescheler, J., Welz, A., Bloch, W., Jacobsen, S. E., and Fleischmann, B. K. (2007) Potential risks of bone marrow cell transplantation into infarcted hearts, Blood, 110, 1362–1369, doi:  https://doi.org/10.1182/blood-2006-12-063412.PubMedCrossRefGoogle Scholar
  13. 13.
    Moll, G., Alm, J. J., Davies, L. C., von Bahr, L., Heldring, N., Stenbeck-Funke, L., Hamad, O. A., Hinsch, R., Ignatowicz, L., Locke, M., Lonnies, H., Lambris, J. D., Teramura, Y., Nilsson-Ekdahl, K., Nilsson, B., and Le Blanc, K. (2014) Do cryopreserved mesenchymal stromal cells display impaired immunomodulatory and therapeutic properties? Stem Cells, 32, 2430–2442, doi:  https://doi.org/10.1002/stem.1729.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Bruno, S., Collino, F., Deregibus, M. C., Grange, C., Tetta, C., and Camussi, G. (2013) Microvesicles derived from human bone marrow mesenchymal stem cells inhibit tumor growth, Stem Cells Dev., 22, 758–771, doi:  https://doi.org/10.1089/scd.2012.0304.PubMedCrossRefGoogle Scholar
  15. 15.
    Wu, S., Ju, G. Q., Du, T., Zhu, Y. J., and Liu, G. H. (2013) Microvesicles derived from human umbilical cord Wharton’s jelly mesenchymal stem cells attenuate bladder tumor cell growth in vitro and in vivo, PloS One, 8, e61366, doi:  https://doi.org/10.1371/journal.pone.0061366.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Qi, J., Zhou, Y., Jiao, Z., Wang, X., Zhao, Y., Li, Y., Chen, H., Yang, L., Zhu, H., and Li, Y. (2017) Exosomes derived from human bone marrow mesenchymal stem cells promote tumor growth through hedgehog signaling pathway, Cell. Physiol. Biochem., 42, 2242–2254, doi:  https://doi.org/10.1159/000479998.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Vallabhaneni, K. C., Penfornis, P., Dhule, S., Guillonneau, F., Adams, K. V., Mo, Y. Y., Xu, R., Liu, Y., Watabe, K., Vemuri, M. C., and Pochampally, R. (2015) Extracellular vesicles from bone marrow mesenchymal stem/stromal cells transport tumor regulatory microRNA, proteins, and metabolites, Oncotarget, 6, 4953–4967, doi:  https://doi.org/10.18632/oncotarget.3211.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Yang, Y., Bucan, V., Baehre, H., von der Ohe, J., Otte, A., and Hass, R. (2015) Acquisition of new tumor cell properties by MSC-derived exosomes, Int. J. Oncol., 47, 244–252, doi:  https://doi.org/10.3892/ijo.2015.3001.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Pascucci, L., Cocce, V., Bonomi, A., Ami, D., Ceccarelli, P., Ciusani, E., Vigano, L., Locatelli, A., Sisto, F., Doglia, S. M., Parati, E., Bernardo, M. E., Muraca, M., Alessandri, G., Bondiolotti, G., and Pessina, A. (2014) Paclitaxel is incorporated by mesenchymal stromal cells and released in exosomes that inhibit in vitro tumor growth: a new approach for drug delivery, J. Control. Release, 192, 262–270, doi:  https://doi.org/10.1016/j.jconrel.2014.07.042.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Vakhshiteh, F., Atyabi, F., and Ostad, S. N. (2019) Mesenchymal stem cell exosomes: a two-edged sword in cancer therapy, Int. J. Nanomed., 14, 2847–2859, doi:  https://doi.org/10.2147/ijn.S200036.CrossRefGoogle Scholar
  21. 21.
    Deng, H., Sun, C., Sun, Y., Li, H., Yang, L., Wu, D., Gao, Q., and Jiang, X. (2018) Lipid, protein, and microRNA composition within mesenchymal stem cell-derived exosomes, Cell. Reprogram., 20, 178–186, doi:  https://doi.org/10.1089/cell.2017.0047.PubMedCrossRefGoogle Scholar
  22. 22.
    Dahbour, S., Jamali, F., Alhattab, D., Al-Radaideh, A., Ababneh, O., Al-Ryalat, N., Al-Bdour, M., Hourani, B., Msallam, M., Rasheed, M., Huneiti, A., Bahou, Y., Tarawneh, E., and Awidi, A. (2017) Mesenchymal stem cells and conditioned media in the treatment of multiple sclerosis patients: clinical, ophthalmological and radiological assessments of safety and efficacy, CNS Neurosci. Ther., 23, 866–874, doi:  https://doi.org/10.1111/cns.12759.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Kordelas, L., Rebmann, V., Ludwig, A. K., Radtke, S., Ruesing, J., Doeppner, T. R., Epple, M., Horn, P. A., Beelen, D. W., and Giebel, B. (2014) MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease, Leukemia, 28, 970–973, doi:  https://doi.org/10.1038/leu.2014.41.PubMedCrossRefGoogle Scholar
  24. 24.
    Nassar, W., El-Ansary, M., Sabry, D., Mostafa, M. A., Fayad, T., Kotb, E., Temraz, M., Saad, A. N., Essa, W., and Adel, H. (2016) Umbilical cord mesenchymal stem cells derived extracellular vesicles can safely ameliorate the progression of chronic kidney diseases, Biomater. Res., 20, 21, doi:  https://doi.org/10.1186/s40824-016-0068-0.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Zhou, B. R., Xu, Y., Guo, S. L., Xu, Y., Wang, Y., Zhu, F., Permatasari, F., Wu, D., Yin, Z. Q., and Luo, D. (2013) The effect of conditioned media of adipose-derived stem cells on wound healing after ablative fractional carbon dioxide laser resurfacing, BioMed Res. Int., 2013, 519126, doi:  https://doi.org/10.1155/2013/519126.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Fukuoka, H., Narita, K., and Suga, H. (2017) Hair regeneration therapy: application of adipose-derived stem cells, Curr. Stem Cell Res. Ther., 12, 531–534, doi:  https://doi.org/10.2174/1574888x12666170522114307.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Shin, H., Won, C. H., Chung, W. K., and Park, B. S. (2017) Up-to-date clinical trials of hair regeneration using conditioned media of adipose-derived stem cells in male and female pattern hair loss, Curr. Stem Cell Res. Ther., 12, 524–530, doi:  https://doi.org/10.2174/1574888x12666170504120244.PubMedCrossRefGoogle Scholar
  28. 28.
    Katagiri, W., Watanabe, J., Toyama, N., Osugi, M., Sakaguchi, K., and Hibi, H. (2017) Clinical study of bone regeneration by conditioned medium from mesenchymal stem cells after maxillary sinus floor elevation, Implant Dent., 26, 607–612, doi:  https://doi.org/10.1097/id.0000000000000618.PubMedCrossRefGoogle Scholar
  29. 29.
    Fujita, Y., Kadota, T., Araya, J., Ochiya, T., and Kuwano, K. (2018) Clinical application of mesenchymal stem cell-derived extracellular vesicle-based therapeutics for inflammatory lung diseases, J. Clin. Med., 7, doi:  https://doi.org/10.3390/jcm7100355.PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Balducci, L., Blasi, A., Saldarelli, M., Soleti, A., Pessina, A., Bonomi, A., Cocce, V., Dossena, M., Tosetti, V., Ceserani, V., Navone, S. E., Falchetti, M. L., Parati, E. A., and Alessandri, G. (2014) Immortalization of human adipose-derived stromal cells: production of cell lines with high growth rate, mesenchymal marker expression and capability to secrete high levels of angiogenic factors, Stem Cell Res. Ther., 5, 63, doi:  https://doi.org/10.1186/scrt452.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Gnecchi, M., He, H., Noiseux, N., Liang, O. D., Zhang, L., Morello, F., Mu, H., Melo, L. G., Pratt, R. E., Ingwall, J. S., and Dzau, V. J. (2006) Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement, FASEB J., 20, 661–669, doi:  https://doi.org/10.1096/fj.05-5211com.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Wang, X., Chen, Y., Zhao, Z., Meng, Q., Yu, Y., Sun, J., Yang, Z., Chen, Y., Li, J., Ma, T., Liu, H., Li, Z., Yang, J., and Shen, Z. (2018) Engineered exosomes with ischemic myocardium-targeting peptide for targeted therapy in myocardial infarction, J. Am. Heart Assoc., 7, e008737, doi:  https://doi.org/10.1161/jaha.118.008737.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Bhang, S. H., Lee, S., Shin, J. Y., Lee, T. J., Jang, H. K., and Kim, B. S. (2014) Efficacious and clinically relevant conditioned medium of human adipose-derived stem cells for therapeutic angiogenesis, Mol. Ther., 22, 862–872, doi:  https://doi.org/10.1038/mt.2013.301.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Kwon, S. H., Bhang, S. H., Jang, H. K., Rhim, T., and Kim, B. S. (2015) Conditioned medium of adipose-derived stromal cell culture in three-dimensional bioreactors for enhanced wound healing, J. Surg. Res., 194, 8–17, doi:  https://doi.org/10.1016/j.jss.2014.10.053.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Xin, H., Katakowski, M., Wang, F., Qian, J. Y., Liu, X. S., Ali, M. M., Buller, B., Zhang, Z. G., and Chopp, M. (2017) MicroRNA cluster miR-17-92 cluster in exosomes enhance neuroplasticity and functional recovery after stroke in rats, Stroke, 48, 747–753, doi:  https://doi.org/10.1161/strokeaha.116.015204.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Yu, B., Kim, H. W., Gong, M., Wang, J., Millard, R. W., Wang, Y., Ashraf, M., and Xu, M. (2015) Exosomes secreted from GATA-4 overexpressing mesenchymal stem cells serve as a reservoir of anti-apoptotic microRNAs for cardioprotection, Int. J. Cardiol., 182, 349–360, doi:  https://doi.org/10.1016/j.ijcard.2014.12.043.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Li, H., Liu, D., Li, C., Zhou, S., Tian, D., Xiao, D., Zhang, H., Gao, F., and Huang, J. (2017) Exosomes secreted from mutant-HIF-1alpha-modified bone-marrow-derived mesenchymal stem cells attenuate early steroid-induced avascular necrosis of femoral head in rabbit, Cell Biol. Int., 41, 1379–1390, doi:  https://doi.org/10.1002/cbin.10869.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Bruno, S., Tapparo, M., Collino, F., Chiabotto, G., Deregibus, M. C., Soares Lindoso, R., Neri, F., Kholia, S., Giunti, S., Wen, S., Quesenberry, P., and Camussi, G. (2017) Renal regenerative potential of different extracellular vesicle populations derived from bone marrow mesenchymal stromal cells, Tissue Eng. Part A, 23, 1262–1273, doi:  https://doi.org/10.1089/ten.TEA.2017.0069.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Wen, S., Dooner, M., Cheng, Y., Papa, E., Del Tatto, M., Pereira, M., Deng, Y., Goldberg, L., Aliotta, J., Chatterjee, D., Stewart, C., Carpanetto, A., Collino, F., Bruno, S., Camussi, G., and Quesenberry, P. (2016) Mesenchymal stromal cell-derived extracellular vesicles rescue radiation damage to murine marrow hematopoietic cells, Leukemia, 30, 2221–2231, doi:  https://doi.org/10.1038/leu.2016.107.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Haga, H., Yan, I. K., Takahashi, K., Matsuda, A., and Patel, T. (2017) Extracellular vesicles from bone marrow-derived mesenchymal stem cells improve survival from lethal hepatic failure in mice, Stem Cells Transl. Med., 6, 1262–1272, doi:  https://doi.org/10.1002/sctm.16-0226.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Lu, H., Poirier, C., Cook, T., Traktuev, D. O., Merfeld-Clauss, S., Lease, B., Petrache, I., March, K. L., and Bogatcheva, N. V. (2015) Conditioned media from adipose stromal cells limit lipopolysaccharide-induced lung injury, endothelial hyperpermeability and apoptosis, J. Transl. Med., 13, 67, doi:  https://doi.org/10.1186/s12967-015-0422-3.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Devaney, J., Horie, S., Masterson, C., Elliman, S., Barry, F., O’Brien, T., Curley, G. F., O’Toole, D., and Laffey, J. G. (2015) Human mesenchymal stromal cells decrease the severity of acute lung injury induced by E. coli in the rat, Thorax, 70, 625–635, doi:  https://doi.org/10.1136/thoraxjnl-2015-206813.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Monsel, A., Zhu, Y. G., Gennai, S., Hao, Q., Hu, S., Rouby, J. J., Rosenzwajg, M., Matthay, M. A., and Lee, J. W. (2015) Therapeutic effects of human mesenchymal stem cell-derived microvesicles in severe pneumonia in mice, Am. J. Respir. Crit. Care Med., 192, 324–336, doi:  https://doi.org/10.1164/rccm.201410-1765OC.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Ahn, S. Y., Park, W. S., Kim, Y. E., Sung, D. K., Sung, S. I., Ahn, J. Y., and Chang, Y. S. (2018) Vascular endothelial growth factor mediates the therapeutic efficacy of mesenchymal stem cell-derived extracellular vesicles against neonatal hyperoxic lung injury, Exp. Mol. Med., 50, 26, doi:  https://doi.org/10.1038/s12276-018-0055-8.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Chaubey, S., Thueson, S., Ponnalagu, D., Alam, M. A., Gheorghe, C. P., Aghai, Z., Singh, H., and Bhandari, V. (2018) Early gestational mesenchymal stem cell secretome attenuates experimental bronchopulmonary dysplasia in part via exosome-associated factor TSG-6, Stem Cell Res. Ther., 9, 173, doi:  https://doi.org/10.1186/s13287-018-0903-4.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Eirin, A., Zhu, X. Y., Jonnada, S., Lerman, A., van Wijnen, A. J., and Lerman, L. O. (2018) Mesenchymal stem cell-derived extracellular vesicles improve the renal microvasculature in metabolic renovascular disease in swine, Cell Transplant., 27, 1080–1095, doi:  https://doi.org/10.1177/0963689718780942.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Meng, Y., Eirin, A., Zhu, X. Y., O’Brien, D. R., Lerman, A., van Wijnen, A. J., and Lerman, L. O. (2018) The metabolic syndrome modifies the mRNA expression profile of extracellular vesicles derived from porcine mesenchymal stem cells, Diabet. Metabol. Syndr., 10, 58, doi:  https://doi.org/10.1186/s13098-018-0359-9.CrossRefGoogle Scholar
  48. 48.
    Reis, L. A., Borges, F. T., Simoes, M. J., Borges, A. A., Sinigaglia-Coimbra, R., and Schor, N. (2012) Bone marrow-derived mesenchymal stem cells repaired but did not prevent gentamicin-induced acute kidney injury through paracrine effects in rats, PloS One, 7, e44092, doi:  https://doi.org/10.1371/journal.pone.0044092.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Zisa, D., Shabbir, A., Suzuki, G., and Lee, T. (2009) Vascular endothelial growth factor (VEGF) as a key therapeutic trophic factor in bone marrow mesenchymal stem cell-mediated cardiac repair, Biochem. Biophys. Res. Commun., 390, 834–838, doi:  https://doi.org/10.1016/j.bbrc.2009.10.058.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Katsuda, T., Tsuchiya, R., Kosaka, N., Yoshioka, Y., Takagaki, K., Oki, K., Takeshita, F., Sakai, Y., Kuroda, M., and Ochiya, T. (2013) Human adipose tissue-derived mesenchymal stem cells secrete functional neprilysin-bound exosomes, Sci. Rep., 3, 1197, doi:  https://doi.org/10.1038/srep01197.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Zhang, B., Wang, M., Gong, A., Zhang, X., Wu, X., Zhu, Y., Shi, H., Wu, L., Zhu, W., Qian, H., and Xu, W. (2015) HucMSC-exosome mediated-Wnt4 signaling is required for cutaneous wound healing, Stem Cells, 33, 2158–2168, doi:  https://doi.org/10.1002/stem.1771.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Zhang, B., Wu, X., Zhang, X., Sun, Y., Yan, Y., Shi, H., Zhu, Y., Wu, L., Pan, Z., Zhu, W., Qian, H., and Xu, W. (2015) Human umbilical cord mesenchymal stem cell exosomes enhance angiogenesis through the Wnt4/betacatenin pathway, Stem Cells Transl. Med., 4, 513–522, doi:  https://doi.org/10.5966/sctm.2014-0267.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Yan, Y., Jiang, W., Tan, Y., Zou, S., Zhang, H., Mao, F., Gong, A., Qian, H., and Xu, W. (2017) HucMSC exosome-derived GPX1 is required for the recovery of hepatic oxidant injury, Mol. Ther., 25, 465–479, doi:  https://doi.org/10.1016/j.ymthe.2016.11.019.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Souza, B. S. F., da Silva, K. N., Silva, D. N., Rocha, V. P. C., Paredes, B. D., Azevedo, C. M., Nonaka, C. K., Carvalho, G. B., Vasconcelos, J. F., Dos Santos, R. R., and Soares, M. B. P. (2017) Galectin-3 knockdown impairs survival, migration, and immunomodulatory actions of mesenchymal stromal cells in a mouse model of Chagas disease cardiomyopathy, Stem Cells Int., 2017, 3282656, doi:  https://doi.org/10.1155/2017/3282656.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Sioud, M., Mobergslien, A., Boudabous, A., and Floisand, Y. (2011) Mesenchymal stem cell-mediated T cell suppression occurs through secreted galectins, Int. J. Oncol., 38, 385–390, doi:  https://doi.org/10.3892/ijo.2010.869.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    He, Y., Zhou, S., Liu, H., Shen, B., Zhao, H., Peng, K., and Wu, X. (2015) Indoleamine 2,3-dioxygenase transfected mesenchymal stem cells induce kidney allograft tolerance by increasing the production and function of regulatory T cells, Transplantation, 99, 1829–1838, doi:  https://doi.org/10.1097/tp.0000000000000856.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Zhang, Q., Fu, L., Liang, Y., Guo, Z., Wang, L., Ma, C., and Wang, H. (2018) Exosomes originating from MSCs stimulated with TGF-beta and IFN-gamma promote Treg differentiation, J. Cell Physiol., 233, 6832–6840, doi:  https://doi.org/10.1002/jcp.26436.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Bruno, S., Grange, C., Deregibus, M. C., Calogero, R. A., Saviozzi, S., Collino, F., Morando, L., Busca, A., Falda, M., Bussolati, B., Tetta, C., and Camussi, G. (2009) Mesenchymal stem cell-derived microvesicles protect against acute tubular injury, J. Am. Soc. Nephrol., 20, 1053–1067, doi:  https://doi.org/10.1681/asn.2008070798.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Gatti, S., Bruno, S., Deregibus, M. C., Sordi, A., Cantaluppi, V., Tetta, C., and Camussi, G. (2011) Microvesicles derived from human adult mesenchymal stem cells protect against ischaemia-reperfusion-induced acute and chronic kidney injury, Nephrol. Dial. Transplant., 26, 1474–1483, doi:  https://doi.org/10.1093/ndt/gfr015.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Harting, M. T., Srivastava, A. K., Zhaorigetu, S., Bair, H., Prabhakara, K. S., Toledano Furman, N. E., Vykoukal, J. V., Ruppert, K. A., Cox, C. S., Jr., and Olson, S. D. (2018) Inflammation-stimulated mesenchymal stromal cell-derived extracellular vesicles attenuate inflammation, Stem Cells, 36, 79–90, doi:  https://doi.org/10.1002/stem.2730.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Collino, F., Bruno, S., Incarnato, D., Dettori, D., Neri, F., Provero, P., Pomatto, M., Oliviero, S., Tetta, C., Quesenberry, P. J., and Camussi, G. (2015) AKI recovery induced by mesenchymal stromal cell-derived extracellular vesicles carrying microRNAs, J. Am. Soc. Nephrol., 26, 2349–2360, doi:  https://doi.org/10.1681/asn.2014070710.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Qiu, G., Zheng, G., Ge, M., Wang, J., Huang, R., Shu, Q., and Xu, J. (2018) Mesenchymal stem cell-derived extracellular vesicles affect disease outcomes via transfer of microRNAs, Stem Cell Res. Ther., 9, 320, doi:  https://doi.org/10.1186/s13287-018-1069-9.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Xin, H., Li, Y., Liu, Z., Wang, X., Shang, X., Cui, Y., Zhang, Z. G., and Chopp, M. (2013) 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, 31, 2737–2746, doi:  https://doi.org/10.1002/stem.1409.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Gu, D., Zou, X., Ju, G., Zhang, G., Bao, E., and Zhu, Y. (2016) Mesenchymal stromal cells derived extracellular vesicles ameliorate acute renal ischemia reperfusion injury by inhibition of mitochondrial fission through miR-30, Stem Cells Int., 2016, 2093940, doi:  https://doi.org/10.1155/2016/2093940.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Feng, Y., Huang, W., Wani, M., Yu, X., and Ashraf, M. (2014) Ischemic preconditioning potentiates the protective effect of stem cells through secretion of exosomes by targeting Mecp2 via miR-22, PloS One, 9, e88685, doi:  https://doi.org/10.1371/journal.pone.0088685.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Wang, X., Gu, H., Qin, D., Yang, L., Huang, W., Essandoh, K., Wang, Y., Caldwell, C. C., Peng, T., Zingarelli, B., and Fan, G. C. (2015) Exosomal miR-223 contributes to mesenchymal stem cell-elicited cardioprotection in polymicrobial sepsis, Sci. Rep., 5, 13721, doi:  https://doi.org/10.1038/srep13721.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Chen, L., Lu, F. B., Chen, D. Z., Wu, J. L., Hu, E. D., Xu, L. M., Zheng, M. H., Li, H., Huang, Y., Jin, X. Y., Gong, Y. W., Lin, Z., Wang, X. D., and Chen, Y. P. (2018) BMSCs-derived miR-223-containing exosomes contribute to liver protection in experimental autoimmune hepatitis, Mol. Immunol., 93, 38–46, doi:  https://doi.org/10.1016/j.molimm.2017.11.008.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Fernandez-Messina, L., Gutierrez-Vazquez, C., Rivas-Garcia, E., Sanchez-Madrid, F., and de la Fuente, H. (2015) Immunomodulatory role of microRNAs transferred by extracellular vesicles, Biol. Cell, 107, 61–77, doi:  https://doi.org/10.1111/boc.201400081.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Hyun, J., Wang, S., Kim, J., Kim, G. J., and Jung, Y. (2015) MicroRNA125b-mediated Hedgehog signaling influences liver regeneration by chorionic plate-derived mesenchymal stem cells, Sci. Rep., 5, 14135, doi:  https://doi.org/10.1038/srep14135.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Wang, B., Yao, K., Huuskes, B. M., Shen, H. H., Zhuang, J., Godson, C., Brennan, E. P., Wilkinson-Berka, J. L., Wise, A. F., and Ricardo, S. D. (2016) Mesenchymal stem cells deliver exogenous microRNA-let7c via exosomes to attenuate renal fibrosis, Mol. Ther., 24, 1290–1301, doi:  https://doi.org/10.1038/mt.2016.90.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Lou, G., Yang, Y., Liu, F., Ye, B., Chen, Z., Zheng, M., and Liu, Y. (2017) MiR-122 modification enhances the therapeutic efficacy of adipose tissue-derived mesenchymal stem cells against liver fibrosis, J. Cell. Mol. Med., 21, 2963–2973, doi:  https://doi.org/10.1111/jcmm.13208.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Fatima, F., Ekstrom, K., Nazarenko, I., Maugeri, M., Valadi, H., Hill, A. F., Camussi, G., and Nawaz, M. (2017) Non-coding RNAs in mesenchymal stem cell-derived extracellular vesicles: deciphering regulatory roles in stem cell potency, inflammatory resolve, and tissue regeneration, Front. Genet., 8, 161, doi:  https://doi.org/10.3389/fgene.2017.00161.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Valadi, H., Ekstrom, K., Bossios, A., Sjostrand, M., Lee, J. J., and Lotvall, J. O. (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells, Nat. Cell Biol., 9, 654–659, doi:  https://doi.org/10.1038/ncb1596.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Zhu, Y. G., Feng, X. M., Abbott, J., Fang, X. H., Hao, Q., Monsel, A., Qu, J. M., Matthay, M. A., and Lee, J. W. (2014) Human mesenchymal stem cell microvesicles for treatment of Escherichia coli endotoxin-induced acute lung injury in mice, Stem Cells, 32, 116–125, doi:  https://doi.org/10.1002/stem.1504.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Kota, D. J., Prabhakara, K. S., Toledano-Furman, N., Bhattarai, D., Chen, Q., DiCarlo, B., Smith, P., Triolo, F., Wenzel, P. L., Cox, C. S., Jr., and Olson, S. D. (2017) Prostaglandin E2 indicates therapeutic efficacy of mesenchymal stem cells in experimental traumatic brain injury, Stem Cells, 35, 1416–1430, doi:  https://doi.org/10.1002/stem.2603.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Ozcan, S., Alessio, N., Acar, M. B., Mert, E., Omerli, F., Peluso, G., and Galderisi, U. (2016) Unbiased analysis of senescence associated secretory phenotype (SASP) to identify common components following different genotoxic stresses, Aging, 8, 1316–1329, doi:  https://doi.org/10.18632/aging.100971.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Sarkar, P., Redondo, J., Kemp, K., Ginty, M., Wilkins, A., Scolding, N. J., and Rice, C. M. (2018) Reduced neuro-protective potential of the mesenchymal stromal cell secretome with ex vivo expansion, age and progressive multiple sclerosis, Cytotherapy, 20, 21–28, doi:  https://doi.org/10.1016/j.jcyt.2017.08.007.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Romanov, Y. A., Volgina, N. E., Dugina, T. N., Kabaeva, N. V., and Sukhikh, G. T. (2019) Effect of storage conditions on the integrity of human umbilical cord mesenchymal stromal cell-derived microvesicles, Bull. Exp. Biol. Med., 167, 131–135, doi:  https://doi.org/10.1007/s10517-019-04476-2.PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Charoenviriyakul, C., Takahashi, Y., Nishikawa, M., and Takakura, Y. (2018) Preservation of exosomes at room temperature using lyophilization, Int. J. Pharm., 553, 1–7, doi:  https://doi.org/10.1016/j.ijpharm.2018.10.032.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Ionescu, L., Byrne, R. N., van Haaften, T., Vadivel, A., Alphonse, R. S., Rey-Parra, G. J., Weissmann, G., Hall, A., Eaton, F., and Thebaud, B. (2012) Stem cell conditioned medium improves acute lung injury in mice: in vivo evidence for stem cell paracrine action, Am. J. Physiol. Lung. Cell. Mol. Physiol., 303, L967–977, doi:  https://doi.org/10.1152/ajplung.00144.2011.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Rathinasabapathy, A., Bruce, E., Espejo, A., Horowitz, A., Sudhan, D. R., Nair, A., Guzzo, D., Francis, J., Raizada, M. K., Shenoy, V., and Katovich, M. J. (2016) Therapeutic potential of adipose stem cell-derived conditioned medium against pulmonary hypertension and lung fibrosis, Br. J. Pharmacol., 173, 2859–2879, doi:  https://doi.org/10.1111/bph.13562.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Ahmadi, M., Rahbarghazi, R., Aslani, M. R., Shahbazfar, A. A., Kazemi, M., and Keyhanmanesh, R. (2017) Bone marrow mesenchymal stem cells and their conditioned media could potentially ameliorate ovalbumin-induced asthmatic changes, Biomed. Pharmacother., 85, 28–40, doi:  https://doi.org/10.1016/j.biopha.2016.11.127.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Parekkadan, B., van Poll, D., Suganuma, K., Carter, E. A., Berthiaume, F., Tilles, A. W., and Yarmush, M. L. (2007) Mesenchymal stem cell-derived molecules reverse fulminant hepatic failure, PloS One, 2, e941, doi:  https://doi.org/10.1371/journal.pone.0000941.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Bi, B., Schmitt, R., Israilova, M., Nishio, H., and Cantley, L. G. (2007) Stromal cells protect against acute tubular injury via an endocrine effect, J. Am. Soc. Nephrol., 18, 2486–2496, doi:  https://doi.org/10.1681/asn.2007020140.PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Kay, A. G., Long, G., Tyler, G., Stefan, A., Broadfoot, S. J., Piccinini, A. M., Middleton, J., and Kehoe, O. (2017) Mesenchymal stem cell-conditioned medium reduces disease severity and immune responses in inflammatory arthritis, Sci. Rep., 7, 18019, doi:  https://doi.org/10.1038/s41598-017-18144-w.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Linero, I., and Chaparro, O. (2014) Paracrine effect of mesenchymal stem cells derived from human adipose tissue in bone regeneration, PloS One, 9, e107001, doi:  https://doi.org/10.1371/journal.pone.0107001.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Fontanilla, C. V., Gu, H., Liu, Q., Zhu, T. Z., Zhou, C., Johnstone, B. H., March, K. L., Pascuzzi, R. M., Farlow, M. R., and Du, Y. (2015) Adipose-derived stem cell conditioned media extends survival time of a mouse model of amyotrophic lateral sclerosis, Sci. Rep., 5, 16953, doi:  https://doi.org/10.1038/srep16953.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Yamagata, M., Yamamoto, A., Kako, E., Kaneko, N., Matsubara, K., Sakai, K., Sawamoto, K., and Ueda, M. (2013) Human dental pulp-derived stem cells protect against hypoxic-ischemic brain injury in neonatal mice, Stroke, 44, 551–554, doi:  https://doi.org/10.1161/strokeaha.112.676759.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Bai, L., Lennon, D. P., Caplan, A. I., DeChant, A., Hecker, J., Kranso, J., Zaremba, A., and Miller, R. H. (2012) Hepatocyte growth factor mediates mesenchymal stem cell-induced recovery in multiple sclerosis models, Nat. Neurosci., 15, 862–870, doi:  https://doi.org/10.1038/nn.3109.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Suto, N., Mieda, T., Iizuka, A., Nakamura, K., and Hirai, H. (2016) Morphological and functional attenuation of degeneration of peripheral neurons by mesenchymal stem cell-conditioned medium in spinocerebellar ataxia type 1-knock-in mice, CNS Neurosci. Ther., 22, 670–676, doi:  https://doi.org/10.1111/cns.12560.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Sun, J., Zhang, Y., Song, X., Zhu, J., and Zhu, Q. (2019) The healing effects of conditioned medium derived from mesenchymal stem cells on radiation-induced skin wounds in rats, Cell Transplant., 28, 105–115, doi:  https://doi.org/10.1177/0963689718807410.PubMedCrossRefGoogle Scholar
  92. 92.
    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., Pasterkamp, G., de Kleijn, D. P., and Lim, S. K. (2010) Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury, Stem Cell Res., 4, 214–222, doi:  https://doi.org/10.1016/j.scr.2009.12.003.PubMedCrossRefGoogle Scholar
  93. 93.
    Gangadaran, P., Rajendran, R. L., Lee, H. W., Kalimuthu, S., Hong, C. M., Jeong, S. Y., Lee, S. W., Lee, J., and Ahn, B. C. (2017) Extracellular vesicles from mesenchymal stem cells activates VEGF receptors and accelerates recovery of hindlimb ischemia, J. Control. Release, 264, 112–126, doi:  https://doi.org/10.1016/j.jconrel.2017.08.022.PubMedCrossRefGoogle Scholar
  94. 94.
    Cosenza, S., Ruiz, M., Toupet, K., Jorgensen, C., and Noel, D. (2017) Mesenchymal stem cells derived exosomes and microparticles protect cartilage and bone from degradation in osteoarthritis, Sci. Rep., 7, 16214, doi:  https://doi.org/10.1038/s41598-017-15376-8.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Doeppner, T. R., Herz, J., Gorgens, A., Schlechter, J., Ludwig, A. K., Radtke, S., de Miroschedji, K., Horn, P. A., Giebel, B., and Hermann, D. M. (2015) Extracellular vesicles improve post-stroke neuroregeneration and prevent postischemic immunosuppression, Stem Cells Transl. Med., 4, 1131–1143, doi:  https://doi.org/10.5966/sctm.2015-0078.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Wang, S. S., Jia, J., and Wang, Z. (2018) Mesenchymal stem cell-derived extracellular vesicles suppresses iNOS expression and ameliorates neural impairment in Alzheimer’s disease mice, J. Alzheimers Dis., 61, 1005–1013, doi:  https://doi.org/10.3233/jad-170848.PubMedCrossRefGoogle Scholar
  97. 97.
    Zhang, Y., Chopp, M., Meng, Y., Katakowski, M., Xin, H., Mahmood, A., and Xiong, Y. (2015) Effect of exosomes derived from multipluripotent mesenchymal stromal cells on functional recovery and neurovascular plasticity in rats after traumatic brain injury, J. Neurosurg., 122, 856–867, doi:  https://doi.org/10.3171/2014.11.Jns14770.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Perets, N., Hertz, S., London, M., and Offen, D. (2018) Intranasal administration of exosomes derived from mesenchymal stem cells ameliorates autistic-like behaviors of BTBR mice, Mol. Autism, 9, 57, doi:  https://doi.org/10.1186/s13229-018-0240-6.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Huang, J. H., Yin, X. M., Xu, Y., Xu, C. C., Lin, X., Ye, F. B., Cao, Y., and Lin, F. Y. (2017) Systemic administration of exosomes released from mesenchymal stromal cells attenuates apoptosis, inflammation, and promotes angiogenesis after spinal cord injury in rats, J. Neurotrauma, 34, 3388–3396, doi:  https://doi.org/10.1089/neu.2017.5063.PubMedCrossRefGoogle Scholar
  100. 100.
    Curley, G. F., Ansari, B., Hayes, M., Devaney, J., Masterson, C., Ryan, A., Barry, F., O’Brien, T., Toole, D. O., and Laffey, J. G. (2013) Effects of intratracheal mesenchymal stromal cell therapy during recovery and resolution after ventilator-induced lung injury, Anesthesiology, 118, 924–932, doi:  https://doi.org/10.1097/ALN.0b013e318287ba08.PubMedCrossRefGoogle Scholar
  101. 101.
    Hayes, M., Curley, G. F., Masterson, C., Devaney, J., O’Toole, D., and Laffey, J. G. (2015) Mesenchymal stromal cells are more effective than the MSC secretome in diminishing injury and enhancing recovery following ventilator-induced lung injury, Intens. Care Med. Exp., 3, 29, doi:  https://doi.org/10.1186/s40635-015-0065-y.CrossRefGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2019

Authors and Affiliations

  1. 1.Division of Pulmonary and Critical Care, Department of MedicineIndiana University School of Medicine, IUPUIIndianapolisUSA
  2. 2.Theratome Bio, Inc.IndianapolisUSA

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