CELL-FREE BIOLOGICS: FOCUS ON MESENCHYMAL STEM CELL CONDITIONED MEDIA
DOI:
https://doi.org/10.32782/2226-2008-2023-4-15Keywords:
cell-free biological agents, conditioned medium, extracellular vesicles, exosomes, culture mediumAbstract
Introduction. The term “conditioned medium” refers to the liquid phase of the cell culture medium enriched with the secretome of the cultured tissue. The culture medium enriched with the secretome from mesenchymal stem cells (MSCs) during their growth was named MSC conditioned medium (MSC-CM). Objective. Summarize the current information on the conditioned medium of mesenchymal stem cells as an innovative cell-free biological tool according to open source data. Methods. Publications were selected based on PubMed, Clinical Key Elsevier, Cochrane Library, eBook Business Collection, and Google Scholar databases, which covered information on the use of MSC-CM as innovative cell-free biological agents. Results. The paradigm shift regarding the mode of action of MSCs contributed to the formation of the concept of cellular secretion, both as a whole concept and as separate fractions, and to a new class of biological therapeutic agents. In recent years, the secret of MSCs has been repeating the path of clinical application of donor cells. MSC secretome is a mixture of biologically active vesicles and individual lipids, proteins and nucleic acids dissolved in the liquid phase. The characteristics of MSC-CM vary depending on the actual source of initial MSCs, gas conditions of cultivation – normoxia or hypoxia, duration of cultivation, etc. The culture medium in in vitro culture represents the microenvironment in vivo and can determine cell fate and thus paracrine properties. Conclusions. The use of MSC-CM has advantages over MSC itself due to the lack of immunogenicity, which allows minimizing interdonor variability and avoiding the need to perform additional procedures in patients for collecting cells.
References
Harrell CR, Fellabaum C, Jovicic N, Djonov V, Arsenijevic N, Volarevic V. Molecular Mechanisms Responsible for Therapeutic Potential of Mesenchymal Stem Cell-Derived Secretome. Cells. 2019;8(5):467. https://doi.org/10.3390/cells8050467
Caplan AI. Mesenchymal Stem Cells: Time to Change the Name! Stem Cells Transl Med. 2017;6(6):1445-1451. https://doi.org/10.1002/sctm.17-0051
Madrigal M, Rao KS, Riordan NH. A review of therapeutic effects of mesenchymal stem cell secretions and induction of secretory modification by different culture methods. J Transl Med. 2014;12:260. https://doi.org/10.1186/s12967-014-0260-8
Yang D, Wang W, Li L, Peng Y, Chen P, Huang H, Guo Y, Xia X, Wang Y, et al. The relative contribution of paracine effect versus direct differentiation on adipose-derived stem cell transplantation mediated cardiac repair. PLoS One. 2013;8(3):e59020. https://doi.org/10.1371/journal.pone.0059020
Gazdic M, Volarevic V, Arsenijevic N, Stojkovic M. Mesenchymal stem cells: a friend or foe in immune-mediated diseases. Stem Cell Rev Rep. 2015;11(2):280-7. https://doi.org/10.1007/s12015-014-9583-3
Pawitan JA. Prospect of stem cell conditioned medium in regenerative medicine. Biomed Res Int. 2014;2014:965849. https://doi.org/10.1155/2014/965849
Maguire G. Stem cell therapy without the cells. Commun Integr Biol. 2013;6(6):e26631. https://doi.org/10.4161/cib.26631
Su X, Upadhyay A, Tran SD, Lin Z. Cell-Free Therapies: The Use of Cell Extracts to Mitigate Irradiation-Injured Salivary Glands. Biology (Basel). 2023;12(2):305. https://doi.org/10.3390/biology12020305
Su X, Liu Y, ElKashty O, Seuntjens J, Yamada KM, Tran SD. Human Bone Marrow Cell Extracts Mitigate Radiation Injury to Salivary Gland. J Dent Res. 2022;101(13):1645-1653. https://doi.org/10.1177/00220345221112332
Su X, Liu Y, ElKashty O, Seuntjens J, Yamada KM, Tran SD. Human Bone Marrow Cell Extracts Mitigate Radiation Injury to Salivary Gland. J Dent Res. 2022;101(13):1645-1653. https://doi.org/10.1177/00220345221112332
Tran SD, Liu Y, Xia D, Maria OM, Khalili S, Wang RW, Quan VH, Hu S, et al. Paracrine effects of bone marrow soup restore organ function, regeneration, and repair in salivary glands damaged by irradiation. PLoS One. 2013;8(4):e61632. https://doi.org/10.1371/journal.pone.0061632
Ra K, Park SC, Lee BC. Female Reproductive Aging and Oxidative Stress: Mesenchymal Stem Cell Conditioned Medium as a Promising Antioxidant. Int J Mol Sci. 2023;24(5):5053. https://doi.org/10.3390/ijms24055053
Andrzejewska A, Lukomska B, Janowski M. Concise Review: Mesenchymal Stem Cells: From Roots to Boost. Stem Cells. 2019;37(7):855-864. https://doi.org/10.1002/stem.3016
Solursh M, Meier S. A conditioned medium (CM) factor produced by chondrocytes that promotes their own differentiation. Dev Biol. 1973;30(2):279-89. https://doi.org/10.1016/0012-1606(73)90089-4
Kim H.O., Choi S.-M., Kim H.-S. Mesenchymal stem cell-derived secretome and microvesicles as a cell-free therapeutics for neurodegenerative disorders. Tissue Eng. Regen. Med. 2013;10:93–101. https://doi.org/10.1007/s13770-013-0010-7
Rosochowicz MA, Lach MS, Richter M, Suchorska WM, Trzeciak T. Conditioned Medium - Is it an Undervalued Lab Waste with the Potential for Osteoarthritis Management? Stem Cell Rev Rep. 2023;19(5):1185-1213. https://doi.org/10.1007/s12015-023-10517-1
Gunawardena TNA, Rahman MT, Abdullah BJJ, Kasim NHA. Conditioned media derived from mesenchymal stem cell cultures: The next generation for regenerative medicine. Journal of Tissue Engineering and Regenerative Medicine. 2019;13(4):569–586. https://doi.org/10.1002/TERM.2806
Kalra H, Drummen GP, Mathivanan S. Focus on Extracellular Vesicles: Introducing the Next Small Big Thing. Int J Mol Sci. 2016;17(2):170. https://doi.org/10.3390/ijms17020170
Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013;200(4):373-83. https://doi.org/10.1083/jcb.201211138
Koniusz S, Andrzejewska A, Muraca M, Srivastava AK, Janowski M, Lukomska B. Extracellular Vesicles in Physiology, Pathology, and Therapy of the Immune and Central Nervous System, with Focus on Extracellular Vesicles Derived from Mesenchymal Stem Cells as Therapeutic Tools. Front Cell Neurosci. 2016;10:109. https://doi.org/10.3389/fncel.2016.00109
Lai FW, Lichty BD, Bowdish DM. Microvesicles: ubiquitous contributors to infection and immunity. J Leukoc Biol. 2015;97(2):237-45. https://doi.org/10.1189/jlb.3RU0513-292RR
Mohan A, Agarwal S, Clauss M, Britt NS, Dhillon NK. Extracellular vesicles: novel communicators in lung diseases. Respir Res. 2020;21(1):175. https://doi.org/10.1186/s12931-020-01423-y
Trams EG, Lauter CJ, Salem N Jr, Heine U. Exfoliation of membrane ecto-enzymes in the form of micro-vesicles. Biochim Biophys Acta. 1981;645(1):63-70. https://doi.org/10.1016/0005-2736(81)90512-5
Harding C, Heuser J, Stahl P. Endocytosis and intracellular processing of transferrin and colloidal gold-transferrin in rat reticulocytes: demonstration of a pathway for receptor shedding. Eur J Cell Biol. 1984;35(2):256-63
Koniusz S, Andrzejewska A, Muraca M, Srivastava AK, Janowski M, Lukomska B. Extracellular Vesicles in Physiology, Pathology, and Therapy of the Immune and Central Nervous System, with Focus on Extracellular Vesicles Derived from Mesenchymal Stem Cells as Therapeutic Tools. Front Cell Neurosci. 2016;10:109. https://doi.org/10.3389/fncel.2016.00109
Giannasi C, Niada S, Della Morte E, Casati S, Orioli M, Gualerzi A, Brini AT. Towards Secretome Standardization: Identifying Key Ingredients of MSC-Derived Therapeutic Cocktail. Stem Cells Int. 2021;2021:3086122. https://doi.org/10.1155/2021/3086122
Yang D., Wang W., Li L., Peng Y., Chen P., Huang H., Guo Y., Xia X., et al. The relative contribution of paracine effect versus direct differentiation on adipose-derived stem cell transplantation mediated cardiac repair. PLoS ONE. 2013;8:e59020.https://doi.org/10.1371/journal.pone.0059020
Bakondi B., Shimada I.S., Perry A., Munoz J.R., Ylostalo J., Howard A.B., Gregory C.A., Spees J.L. CD133 identifies a human bone marrow stem/progenitor cell sub-population with a repertoire of secreted factors that protect against stroke. Mol. Ther. 2009;17:1938–1947. https://doi.org/10.1038/mt.2009.185
Cantinieaux D., Quertainmont R., Blacher S., Rossi L., Wanet T., Noel A., Brook G., Schoenen J., Franzen R. Conditioned medium from bone marrow-derived mesenchymal stem cells improves recovery after spinal cord injury in rats: An original strategy to avoid cell transplantation. PLoS ONE. 2013;8:e69515. https://doi.org/10.1371/journal.pone.0069515
Chang C.P., Chio C.C., Cheong C.U., Chao C.M., Cheng B.C., Lin M.T. Hypoxic preconditioning enhances the therapeutic potential of the secretome from cultured human mesenchymal stem cells in experimental traumatic brain injury. Clin. Sci. 2013;124:165–176. https://doi.org/10.1042/CS20120226
Mishra P.J., Mishra P.J., Banerjee D. Cell-free derivatives from mesenchymal stem cells are effective in wound therapy. World J. Stem Cells. 2012;4:35–43. https://doi.org/10.4252/wjsc.v4.i5.35
Du Z., Wei C., Cheng K., Han B., Yan J., Zhang M., Peng C., Liu Y. Mesenchymal stem cell-conditioned medium reduces liver injury and enhances regeneration in reduced-size rat liver transplantation. J. Surg. Res. 2013;183:907–915. https://doi.org/10.1016/j.jss.2013.02.009
Koppen A., Joles J.A., van Balkom B.W., Lim S.K., de Kleijn D., Giles R.H., Verhaar M.C. Human embryonic mesenchymal stem cell-derived conditioned medium rescues kidney function in rats with established chronic kidney disease. PLoS ONE. 2012;7:e38746. https://doi.org/10.1371/journal.pone.0038746
Kawai T., Katagiri W., Osugi M., Sugimura Y., Hibi H., Ueda M. Secretomes from bone marrow-derived mesenchymal stromal cells enhance periodontal tissue regeneration. Cytotherapy. 2015;17:369–381. https://doi.org/10.1016/j.jcyt.2014.11.009
Osugi M., Katagiri W., Yoshimi R., Inukai T., Hibi H., Ueda M. Conditioned media from mesenchymal stem cells enhanced bone regeneration in rat calvarial bone defects. Tissue Eng. Part A. 2012;18:1479–1489. https://doi.org/10.1089/ten.tea.2011.0325
Veronesi F., Borsari V., Sartori M., Orciani M., Mattioli-Belmonte M., Fini M. The use of cell conditioned medium for musculoskeletal tissue regeneration. J. Cell. Physiol. 2018;233:4423–4442. https://doi.org/10.1002/jcp.26291
Montero-Vilchez T., Sierra-Sanchez A., Sanchez-Diaz M., Quinones-Vico M.I., Sanabria-de-la-Torre R., Martinez-Lopez A., Arias-Santiago S. Mesenchymal Stromal Cell-Conditioned Medium for Skin Diseases: A Systematic Review. Front. Cell Dev. Biol. 2021;9:654210. https://doi.org/10.3389/fcell.2021.654210
Sagaradze G.D., Basalova N.A., Kirpatovsky V.I., Ohobotov D.A., Grigorieva O.A., Balabanyan V.Y., Kamalov A.A., Efimenko A.Y. Application of rat cryptorchidism model for the evaluation of mesenchymal stromal cell secretome regenerative potential. Biomed. Pharmacother. 2019;109:1428–1436. https://doi.org/10.1016/j.biopha.2018.10.174
Kay A.G., Long G., Tyler G., Stefan A., Broadfoot S.J., Piccinini A.M., Middleton J., Kehoe O. Mesenchymal Stem Cell-Conditioned Medium Reduces Disease Severity and Immune Responses in Inflammatory Arthritis. Sci. Rep. 2017;7:18019. https://doi.org/10.1038/s41598-017-18144-w
Dahbour S., Jamali F., Alhattab D., Al-Radaideh A., Ababneh O., Al-Ryalat N., Al-Bdour M., Hourani B., Msallam M., Rasheed M., et al. 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. 2017;23:866–874. https://doi.org/10.1111/cns.12759
Gunawardena TNA, Rahman MT, Abdullah BJJ, Abu Kasim NH. Conditioned media derived from mesenchymal stem cell cultures: The next generation for regenerative medicine. J Tissue Eng Regen Med. 2019;13(4):569-586. https://doi.org/10.1002/term.2806
Maguire G. Stem cell therapy without the cells. Commun Integr Biol. 2013;6(6):e26631. https://doi.org/10.4161/cib.26631
Chuang TJ, Lin KC, Chio CC, Wang CC, Chang CP, Kuo JR. Effects of secretome obtained from normoxiapreconditioned human mesenchymal stem cells in traumatic brain injury rats. Journal of Trauma and Acute Care Surgery. 2012;73(5):1161–1167. https://doi.org/10.1097/TA.0B013E318265D128
Marlina, M., Armenia, A., Rahmadian, R., Aviani, J. K., Sholihah, I. A., Kusuma, H. S. W., Widowati, W. Conditioned Medium of IGF1-Induced Synovial Membrane Mesenchymal Stem Cells Increases Chondrogenic and Chondroprotective Markers in Chondrocyte Inflammation. Bioscience Reports, 2021;41(7),BSR20202038. https://doi.org/10.1042/BSR20202038
Chuang T. J., Lin K. C., Chio C. C., Wang C. C., Chang C. P., Kuo J. R. Effects of secretome obtained from normoxiapreconditioned human mesenchymal stem cells in traumatic brain injury rats. Journal of Trauma and Acute Care Surgery. 2012;73(5):1161–1167. https://doi.org/10.1097/TA.0b013e318265d128
Chang C., Chio C., Cheong C., Chao C., Cheng B., Lin M. Hypoxic preconditioning enhances the therapeutic potential of the secretome from cultured human mesenchymal stem cells in experimental traumatic brain injury. Clinical Science. 2013;124(3):165–176. https://doi.org/10.1042/CS20120226
Inoue T., Sugiyama M., Hattori H., Wakita H., Wakabayashi T., Ueda M. Stem cells from human exfoliated deciduous toothderived conditioned medium enhance recovery of focal cerebral ischemia in rats. Tissue Engineering A. 2013;19(1-2):24–29. https://doi.org/10.1089/ten.tea.2011.0385
Ho J. C. Y., Lai W., Li M., Au K., Yip M., Wong N. L. Y., Ng E. S. K., Lam F. F. Y., et al. Reversal of endothelial progenitor cell dysfunction in patients with type 2 diabetes using a conditioned medium of human embryonic stem cell-derived endothelial cells. Diabetes/Metabolism Research and Reviews. 2012;28(5):462–473. https://doi.org/10.1002/dmrr.2304
Cho Y. J., Song H. S., Bhang S., Lee S., Kang B. G., Lee J. C., An J., Cha C. I., et al. Therapeutic effects of human adipose stem cell-conditioned medium on stroke. Journal of Neuroscience Research. 2012;90(9):1794–1802. https://doi.org/10.1002/jnr.23063
Bhang S. H., Lee S., Shin J. Y., Lee T. J., Jang H. K., Kim B. S. Efficacious and clinically relevant conditioned-medium of human adipose-derived stem cells for therapeutic angiogenesis. Molecular Therapy. 2014;22(4):862.
Golubinskaya P.A., Sarycheva M.V., Dolzhikov A.A., Bondarev V.P., Stefanova M.S., Soldatov V.O., Nadezhdin S.V., Korokin M.V., et al. Application of multipotent mesenchymal stem cell secretome in the treatment of adjuvant arthritis and contact-allergic dermatitis in animal models. Pharmacy & Pharmacology. 2020;8(6):416-425. https://doi.org/10.19163/2307-9266-2020-8-6-416-425
Gieseke F, Böhringer J, Bussolari R, Dominici M, Handgretinger R, Müller I. Human multipotent mesenchymal stromal cells use galectin-1 to inhibit immune effector cells. Blood. 2010;116(19):3770–3779. https://doi.org/10.1182/blood-2010-02-270777
