№ 4 (185) 2023 р. С. 75–82

БЕЗКЛІТИННІ БІОЛОГІЧНІ ЗАСОБИ: ФОКУС НА КОНДИЦІОНОВАНІ СЕРЕДОВИЩА МЕЗЕНХІМАЛЬНИХ СТОВБУРОВИХ КЛІТИН

Харківський національний університет імені В. Н. Каразіна, Харків, Україна
Державна установа «Інститут медичної радіолоґії та онколоґії імені С. П. Григор’єва Національної академії медичних наук України», Харків, Україна
Інститут проблем кріобіолоґії і кріомедицини Національної академії наук України, Харків, Україна

DOI 10.32782/2226-2008-2023-4-15

Огляд присвячено узагальненню сучасних відомостей про кондиціоновані середовища мезенхімальних стовбурових клітин (КС-МСК), як інноваційний безклітинний біологічний засіб. Термін «кондиціоноване середовище» належить до рідкої фази серед- овища клітинної культури, збагаченої секретомом культивованих клітин. Характеристики КС-МСК різняться залежно від власне джерела вихідних МСК (кістковий мозок, жирова тканина, плацента та ін.), газових умов культивування – нормоксія (O2 20,0–21,0 %) або гіпоксія (0,5–1,0–1,5–2,0 % О2), тривалості культивування (від 16–24–48–72 годин до 3–5 днів) та ін. Культуральне середовище в культурі in vitro являє собою мікрооточення в умовах in vivo та може визначати долю клітин і, таким чином, їхні паракринні влас- тивості. Застосування КС-МС має переваги над власне МСК за рахунок відсутності імуногенності. Натепер у світі зареєстровано 14 клінічних досліджень щодо ефективності кондиціонованих середовищ.

Ключові слова: безклітинні біологічні засоби, кондиціоноване середовище, позаклітинні везикули, екзосоми, культиваційне середовище.

REFERENCES

  1. Harrell CR, Fellabaum C, Jovicic N, Djonov V, Arsenijevic N, Volarevic Molecular Mechanisms Responsible for Therapeutic Potential of Mesenchymal Stem Cell-Derived Secretome. Cells. 2019;8(5):467. https://doi.org/10.3390/cells8050467
  2. Caplan 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
  3. Madrigal M, Rao KS, Riordan NH. A review of therapeutic effects of mesenchymal stem cell secretions and induction of secretory modification by different culture J Transl Med. 2014;12:260. https://doi.org/10.1186/s12967-014-0260-8
  4. 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
  5. Gazdic M, Volarevic V, Arsenijevic N, Stojkovic M. Mesenchymal stem cells: a friend or foe in immune-mediated Stem Cell Rev Rep. 2015;11(2):280-7. https://doi.org/10.1007/s12015-014-9583-3
  6. Pawitan JA. Prospect of stem cell conditioned medium in regenerative medicine. Biomed Res Int. 2014;2014:965849. https://doi.org/10.1155/2014/965849
  7. Maguire Stem cell therapy without the cells. Commun Integr Biol. 2013;6(6):e26631. https://doi.org/10.4161/cib.26631
  8. Su X, Upadhyay A, Tran SD, Lin Z. Cell-Free Therapies: The Use of Cell Extracts to Mitigate Irradiation-Injured Salivary Biology (Basel). 2023;12(2):305. https://doi.org/10.3390/biology12020305
  9. Su X, Liu Y, ElKashty O, Seuntjens J, Yamada KM, Tran 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
  10. Su X, Liu Y, ElKashty O, Seuntjens J, Yamada KM, Tran 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
  11. Tran SD, Liu Y, Xia D, Maria OM, Khalili S, Wang RW, Quan VH, Hu S, et 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
  12. Ra K, Park SC, Lee BC. Female Reproductive Aging and Oxidative Stress: Mesenchymal Stem Cell Conditioned Medium as a Promising Int J Mol Sci. 2023;24(5):5053. https://doi.org/10.3390/ijms24055053
  13. 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
  14. Solursh M, Meier S. A conditioned medium (CM) factor produced by chondrocytes that promotes their own Dev Biol. 1973;30(2):279-89. https://doi.org/10.1016/0012-1606(73)90089-4
  15. Kim H.O., Choi S.-M., Kim H.-S. Mesenchymal stem cell-derived secretome and microvesicles as a cell-free therapeutics for neurodegenerative Tissue Eng. Regen. Med. 2013;10:93–101. https://doi.org/10.1007/s13770-013-0010-7
  16. Rosochowicz MA, Lach MS, Richter M, Suchorska WM, Trzeciak 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
  17. 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
  18. Kalra H, Drummen GP, Mathivanan Focus on Extracellular Vesicles: Introducing the Next Small Big Thing. Int J Mol Sci. 2016;17(2):170. https://doi.org/10.3390/ijms17020170
  19. 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
  20. 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 Front Cell Neurosci. 2016;10:109. https://doi.org/10.3389/fncel.2016.00109
  21. 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
  22. Mohan A, Agarwal S, Clauss M, Britt NS, Dhillon Extracellular vesicles: novel communicators in lung diseases. Respir Res. 2020;21(1):175. https://doi.org/10.1186/s12931-020-01423-y
  23. Trams EG, Lauter CJ, Salem N Jr, Heine 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
  24. 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 Eur J Cell Biol. 1984;35(2):256-63
  25. 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 Front Cell Neurosci. 2016;10:109. https://doi.org/10.3389/fncel.2016.00109
  26. 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 Stem Cells Int. 2021;2021:3086122. https://doi. org/10.1155/2021/3086122
  27. Yang , 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
  28. 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. Ther. 2009;17:1938–1947. https://doi.org/10.1038/mt.2009.185
  29. Cantinieaux D., Quertainmont R., Blacher , 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
  30. Chang 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
  31. Mishra P.J., Mishra P.J., Banerjee D. Cell-free derivatives from mesenchymal stem cells are effective in wound therapy. World Stem Cells. 2012;4:35–43. https://doi.org/10.4252/wjsc.v4.i5.35
  32. 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 J. Surg. Res. 2013;183:907–915. https://doi. org/10.1016/j.jss.2013.02.009
  33. Koppen , 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
  34. Kawai , 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
  35. Osugi , 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
  36. Veronesi F., Borsari V., Sartori M., Orciani M., Mattioli-Belmonte M., Fini M. The use of cell conditioned medium for musculoskeletal tissue J. Cell. Physiol. 2018;233:4423–4442. https://doi.org/10.1002/jcp.26291
  37. Montero-Vilchez T., Sierra-Sanchez A., Sanchez-Diaz M., Quinones-Vico M.I., Sanabria-de-la-Torre R., Martinez-Lopez , 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
  38. 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 Biomed. Pharmacother. 2019;109:1428–1436. https://doi.org/10.1016/j.biopha.2018.10.174
  39. 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
  40. 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
  41. Gunawardena TNA, Rahman MT, Abdullah BJJ, Abu Kasim 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
  42. Maguire Stem cell therapy without the cells. Commun Integr Biol. 2013;6(6):e26631. https://doi.org/10.4161/cib.26631
  43. Chuang TJ, Lin KC, Chio CC, Wang CC, Chang CP, Kuo JR. Effects of secretome obtained from normoxia- preconditioned 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
  44. Marlina, , 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
  45. Chuang T. J., Lin K. C., Chio C. C., Wang C. C., Chang C. P., Kuo J. R. Effects of secretome obtained from normoxia- preconditioned 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
  46. Chang , 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
  47. Inoue , Sugiyama M., Hattori H., Wakita H., Wakabayashi T., Ueda M. Stem cells from human exfoliated deciduous tooth- derived 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
  48. Ho 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
  49. 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
  50. 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 Molecular Therapy. 2014;22(4):862.
  51. 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/10.19163/2 307-9266-2020-8-6-416-425
  52. 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