Biomedical Chemistry: Research and Methods 2024, 7(3), e00221

Efferocytosis as One of the Mechanisms for Realizing the Therapeutic Effects of Mesenchymal Stem Cells

G.A. Blinova, K.N. Yarygin, I.V. Kholodenko*

Institute of Biomedical Chemistry, Pogodinskaya Street, 10, Moscow 119121, Russia; *e-mail: irkhol@yandex.ru

Keywords: efferocytosis; apoptosis; mesenchymal stem cells; inflammation; regeneration; immunomodulation

DOI:10.18097/BMCRM00221

The whole version of this paper is available in Russian.

Mesenchymal stem cells (MSCs) stimulate regeneration and exhibit unique immunomodulatory properties, which makes them attractive for use in cell therapies of a wide range of pathologies. The clinical use of MSCs is hampered by the insufficiently clear understanding of their therapeutic action mechanisms. It has been reliably proven that MSCs after transplantation quickly die in the recipient’s body by the mechanism of apoptosis and are cleared by professional, such as macrophages, and non-professional phagocytes, including endothelial cells, hepatocytes, resident stem cells of various tissues, including MSCs. The ingestion and processing of apoptotic cells by the phagocytes was named efferocytosis. Despite rapid elimination of transplanted cells, in most cases MSC transplantation leads to positive therapeutic effects. Clearance of apoptotic MSCs affects phagocytes, changing their phenotype, secretome, and further behavior. This review presents the basic molecular mechanisms of efferocytosis, examines the clearance of apoptotic MSCs and their therapeutic effects in various pathologies in the context of their efferocytosis by various types of phagocytes.
Figure 1. Stages of apoptotic cell efferocytosis. Description in the text (available in Russian).
Figure 2. Mechanisms of therapeutic effects of apoptotic mesenchymal stem cells.

FUNDING

The research was supported by the Russian Science Foundation grant No. 23-15-00149.

REFERENCES

  1. Fuchs, Y., Steller, H. (2011) Programmed cell death in animal development and disease. Cell, 147(4), 742–758. DOI
  2. Yeo, W., Gautier, J. (2004) Early neural cell death: Dying to become neurons. Dev. Biol. 274(2), 233–244. DOI
  3. Varela-Nieto, I., Palmero, I., Magariños, M. (2019) Complementary and distinct roles of autophagy, apoptosis and senescence during early inner ear development. Hear. Res., 376, 86–96. DOI
  4. Blume, Z.I., Lambert, J.M., Lovel, A.G., Mitchell, D.M. (2020) Microglia in the developing retina couple phagocytosis with the progression of apoptosis via P2RY12 signaling. Dev. Dyn., 249(6), 723–740. DOI
  5. Jahnukainen, K., Chrysis, D., Hou, M., Parvinen, M., Eksborg, S., Söder,O. (2004) Increased apoptosis occurring during the first wave of spermatogenesis is stage-specific and primarily affects midpachytene spermatocytes in the rat testis. Biol. Reprod., 70(2), 290–296. DOI
  6. Li, A., Felix, J.C., Hao, J., Minoo, P., Jain, J.K. (2005) Menstrual-like breakdown and apoptosis in human endometrial explants. Hum. Reprod., 20(6), 1709–1719. DOI
  7. Zhang, N., Hartig, H., Dzhagalov, I., Draper, D., He, Y.W. (2005) The role of apoptosis in the development and function of T lymphocytes. Cell Res., 15(10), 749–769. DOI
  8. Comi, C., Fleetwood, T., Dianzani, U. (2012)The role of T cell apoptosis in nervous system autoimmunity. Autoimmun. Rev., 12(2), 150–156. DOI
  9. Casamayor-Polo, L., López-Nevado, M., Paz-Artal, E., Anel, A., Rieux-Laucat, F., Allende, L.M. (2021) Immunologic evaluation and genetic defects of apoptosis in patients with autoimmune lymphoproliferative syndrome (ALPS). Crit. Rev. Clin. Lab. Sci., 58(4), 253–274. DOI
  10. Cassim, A., Hettiarachchi, D., Dissanayake, V.H.W. (2022) Genetic determinants of syndactyly: Perspectives on pathogenesis and diagnosis. Orphanet J. Rare Dis., 17(1), 198. DOI
  11. Avagliano, L., Doi, P., Tosi, D., Scagliotti, V., Gualtieri, A., Gaston-Massuet, C., Pistocchi, A., Gallina, A., Marconi, A.M., Bulfamante, G., Massa, V. (2016) Cell death and cell proliferation in human spina bifida. Birth Defects Res. A Clin. Mol. Teratol., 106(2), 104–113. DOI
  12. Pistritto, G., Trisciuoglio, D., Ceci, C., Garufi, A., d'Orazi, G. (2016) Apoptosis as anticancer mechanism: Function and dysfunction of its modulators and targeted therapeutic strategies. Aging (Albany NY), 8(4), 603–619. DOI
  13. Han, C.Z., Ravichandran, K.S. (2011) Metabolic connections during apoptotic cell engulfment. Cell, 147(7), 1442–1445. DOI
  14. Boada-Romero E., Martinez J., Heckmann B.L., Green D.R. (2020) The clearance of dead cells by efferocytosis. Nat. Rev. Mol. Cell Biol., 21(7), 398–414. DOI
  15. Juban, G., Chazaud, B. (2021) Efferocytosis during skeletal muscle regeneration. Cells, 10(12), 3267. DOI
  16. Kholodenko, I.V., Yarygin, K.N. (2023) Hepatic macrophages as targets for the MSC-based cell therapy in non-alcoholic steatohepatitis. Biomedicines, 11(11), 3056. DOI
  17. Wang, X., He, Q., Zhou, C., Xu, Y., Liu, D., Fujiwara, N., Kubota, N., Click, A., Henderson, P., Vancil, J., Marquez, C.A., Gunasekaran, G., Schwartz, M.E., Tabrizian, P., Sarpel, U., Fiel, M.I., Diao, Y., Sun, B., Hoshida, Y., Liang, S., Zhong, Z. (2023) Prolonged hypernutrition impairs TREM2-dependent efferocytosis to license chronic liver inflammation and NASH development. Immunity, 56(1), 58–77.e11. DOI
  18. Zhang, S., Weinberg, S., deBerge, M., Gainullina, A., Schipma, M., Kinchen, J.M., Ben-Sahra, I., Gius, D.R., Yvan-Charvet, L., Chandel, N.S., Schumacker, P.T., Thorp, E.B. (2019) Efferocytosis fuels requirements of fatty acid oxidation and the electron transport chain to polarize macrophages for tissue repair. Cell Metab., 29(2), 443–456.e5. DOI
  19. Brandel, V., Schimek, V., Göber, S., Hammond, T., Brunnthaler, L., Schrottmaier, W.C., Mussbacher, M., Sachet, M., Liang, Y.Y., Reipert, S., Ortmayr, G., Pereyra, D., Santol, J., Rainer, M., Walterskirchen, N., Ramos, C., Gerakopoulos, V., Rainer, C., Spittler, A., Weiss, T., Kain, R., Messner, B., Gruenberger, T., Assinger, A., Oehler, R., Starlinger, P. (2022) Hepatectomy-induced apoptotic extracellular vesicles stimulate neutrophils to secrete regenerative growth factors. J. Hepatol., 77(6), 1619–1630. DOI
  20. Kholodenko, I.V., Kholodenko, R.V., Majouga, A.G., Yarygin, K.N. (2022) Apoptotic MSCs and MSC-derived apoptotic bodies as new therapeutic tools. Curr. Issues Mol. Biol., 44(11), 5153–5172. DOI
  21. Preda, M.B., Neculachi, C.A., Fenyo, I.M., Vacaru, A.M., Publik, M.A., Simionescu, M., Burlacu, A. (2021) Short lifespan of syngeneic transplanted MSC is a consequence of in vivo apoptosis and immune cell recruitment in mice. Cell Death Dis., 12(6), 566. DOI
  22. Lu, W., Fu, C., Song, L., Yao, Y., Zhang, X., Chen, Z., Li, Y., Ma, G., Shen, C. (2013) Exposure to supernatants of macrophages that phagocytized dead mesenchymal stem cells improves hypoxic cardiomyocytes survival. Int. J. Cardiol., 165, 333–340. DOI
  23. Wagoner, Z.W., Zhao, W. (2021) Therapeutic implications of transplanted-cell death. Nat. Biomed. Eng., 5(5), 379–384. DOI
  24. Elliott, M.R., Koster, K.M., Murphy, P.S. (2017) Efferocytosis signaling in the regulation of macrophage inflammatory responses. J. Immunol., 198(4), 1387–1394. DOI
  25. Kelley, S.M., Ravichandran, K.S. (2021) Putting the brakes on phagocytosis: “Don't-eat-me” signaling in physiology and disease. EMBO Rep., 22(6), e52564. DOI
  26. Azuma, Y., Nakagawa, H., Dote, K., Higai, K., Matsumoto, K. (2011) Decreases in CD31 and CD47 levels on the cell surface during etoposide-induced Jurkat cell apoptosis. Biol. Pharm. Bull., 34(12), 1828–1834. DOI
  27. Tada, K., Tanaka, M., Hanayama, R., Miwa, K., Shinohara, A., Iwamatsu, A., Nagata, S. (2003) Tethering of apoptotic cells to phagocytes through binding of CD47 to Src homology 2 domain-bearing protein tyrosine phosphatase substrate-1. J. Immunol., 171(11), 5718–5726. DOI
  28. Lv, Z., Bian, Z., Shi, L., Niu, S., Ha, B., Tremblay, A., Li, L., Zhang, X., Paluszynski, J., Liu, M., Zen, K., Liu, Y. (2015) Loss of cell surface CD47 clustering formation and binding avidity to SIRPα facilitate apoptotic cell clearance by macrophages. J. Immunol., 195(2), 661–671. DOI
  29. Shi, H., Wang, X., Li, F., Gerlach, B.D., Yurdagul, A. Jr, Moore, M.P., Zeldin, S., Zhang, H., Cai, B., Zheng, Z., Valenti, L., Tabas, I. (2022) CD47-SIRPα axis blockade in NASH promotes necroptotic hepatocyte clearance by liver macrophages and decreases hepatic fibrosis. Sci. Transl. Med., 14(672), eabp8309. DOI
  30. Jarr, K.U., Kojima, Y., Weissman, I.L., Leeper, N.J. (2022) 2021 Jeffrey M. Hoeg Award lecture: Defining the role of efferocytosis in cardiovascular disease: A focus on the CD47 (Cluster of Differentiation 47) axis. Arterioscler. Thromb. Vasc. Biol., 42(6), e145–e154. DOI
  31. von Roemeling, C.A., Wang, Y., Qie, Y., Yuan, H., Zhao, H., Liu, X., Yang, Z., Yang, M., Deng, W., Bruno, K.A., Chan, C.K., Lee, A.S., Rosenfeld, S.S., Yun, K., Johnson, A.J., Mitchell, D.A., Jiang, W., Kim, B.Y.S. (2020) Therapeutic modulation of phagocytosis in glioblastoma can activate both innate and adaptive antitumour immunity. Nat. Commun., 11(1), 1508. DOI
  32. Zhang, J., Jin, S., Guo, X., Qian, W. (2018) Targeting the CD47-SIRPα signaling axis: Current studies on B-cell lymphoma immunotherapy. J. Int. Med. Res., 46(11), 4418–4426. DOI
  33. Xu, R., Xie, H., Shen, X., Huang, J., Zhang, H., Fu, Y., Zhang, P., Guo, S., Wang, D., Li, S., Zheng, K., Sun, W., Liu, L., Cheng, J., Jiang, H. (2023) Impaired efferocytosis enables apoptotic osteoblasts to escape osteoimmune surveillance during aging. Adv. Sci., 10(36), e2303946. DOI
  34. Bratton, D.L., Fadok, V.A., Richter, D.A., Kailey, J.M., Guthrie, L.A., Henson, P.M. (1997) Appearance of phosphatidylserine on apoptotic cells requires calcium-mediated nonspecific flip-flop and is enhanced by loss of the aminophospholipid translocase. J. Biol. Chem., 272(42), 26159–26165. DOI
  35. Birge, R.B., Boeltz, S., Kumar, S., Carlson, J.,Wanderley, J., Calianese, D., Barcinski, M., Brekken, R.A., Huang, X., Hutchins, J.T., Freimark, B., Empig, C., Mercer, J., Schroit, A.J., Schett, G., Herrmann, M. (2016) Phosphatidylserine is a global immunosuppressive signal in efferocytosis, infectious disease, and cancer. Cell Death Differ., 23(6), 962–978. DOI
  36. Gardai, S.J., McPhillips, K.A., Frasch, S.C., Janssen, W.J., Starefeldt, A., Murphy-Ullrich, J.E., Bratton, D.L., Oldenborg, P.A., Michalak, M., Henson, P.M. (2005) Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell, 123(2), 321–334. DOI
  37. Bohlson, S.S., Fraser, D.A., Tenner, A.J. (2006) Complement proteins C1q and MBL are pattern recognition molecules that signal immediate and long-term protective immune functions. Mol. Immunol., 44(1–3), 33–43. DOI
  38. Oroszlán, M., Daha, M.R., Cervenak, L., Prohászka, Z., Füst, G., Roos, A. (2007) MBL and C1q compete for interaction with human endothelial cells. Mol. Immunol., 44(6), 1150–1158. DOI
  39. Ogden, C.A., de Cathelineau, A., Hoffmann, P.R., Bratton, D., Ghebrehiwet, B., Fadok, V.A., Henson, P.M. (2001) C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells. J. Exp. Med., 194(6), 781–795. DOI
  40. Meesmann, H.M., Fehr, E.M., Kierschke, S., Herrmann, M., Bilyy, R., Heyder, P., Blank, N., Krienke, S., Lorenz, H.M., Schiller, M. (2010) Decrease of sialic acid residues as an eat-me signal on the surface of apoptotic lymphocytes. J. Cell Sci., 123(Pt 19), 3347–3356. DOI
  41. Kinchen, J.M., Ravichandran, K.S. (2007) Journey to the grave: Signaling events regulating removal of apoptotic cells. J. Cell Sci., 120(Pt 13), 2143–2149. DOI
  42. Gutierrez, M.G. (2013) Functional role(s) of phagosomal Rab GTPases. Small GTPases, 4(3), 148–158. DOI
  43. Christoforidis, S., McBride, H.M., Burgoyne, R.D., Zerial, M. (1999) The Rab5 effector EEA1 is a core component of endosome docking. Nature, 397(6720), 621–625. DOI
  44. Fratti, R.A., Backer, J.M., Gruenberg, J., Corvera, S., Deretic, V. (2001) Role of phosphatidylinositol 3-kinase and Rab5 effectors in phagosomal biogenesis and mycobacterial phagosome maturation arrest. J. Cell Biol., 154(3), 631–644. DOI
  45. Kaur, G., Lakkaraju, A. (2018) Early endosome morphology in health and disease. Adv. Exp. Med. Biol., 1074, 335–343. DOI
  46. Vieira, O.V., Botelho, R.J., Rameh, L., Brachmann, S.M., Matsuo, T., Davidson, H.W., Schreiber, A., Backer, J.M., Cantley, L.C., Grinstein, S. (2001) Distinct roles of class I and class III phosphatidylinositol 3-kinases in phagosome formation and maturation. J. Cell Biol., 155(1), 19–25. DOI
  47. Vieira, O.V., Bucci, C., Harrison, R.E., Trimble, W.S., Lanzetti, L., Gruenberg, J., Schreiber, A.D., Stahl, P.D., Grinstein, S. (2003) Modulation of Rab5 and Rab7 recruitment to phagosomes by phosphatidylinositol 3-kinase. Mol. Cell. Biol., 23(7), 2501–2514. DOI
  48. Fairn, G.D., Grinstein, S. (2012) How nascent phagosomes mature to become phagolysosomes. Trends Immunol., 33(8), 397–405. DOI
  49. Kinchen, J.M., Ravichandran, K.S. (2008) Phagosome maturation: Going through the acid test. Nat. Rev. Mol. Cell Biol., 9(10), 781–795. DOI
  50. Huynh, K.K., Eskelinen, E.L., Scott, C.C., Malevanets, A., Saftig, P., Grinstein, S. (2007) LAMP proteins are required for fusion of lysosomes with phagosomes. EMBO J., 26(2), 313–324. DOI
  51. Dominici,M., le Blanc, K., Mueller, I., Slaper-Cortenbach, I., Marini, F., Krause, D., Deans, R., Keating, A., Prockop, Dj., Horwitz, E. (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy, 8(4), 315–317. DOI
  52. Tsvetkova, A.V., Vakhrushev, I.V., Basok, Y.B., Grigor'ev, A.M., Kirsanova, L.A., Lupatov, A.Y., Sevastianov, V.I., Yarygin, K.N. (2021) Chondrogeneic potential of MSC from different sources in spheroid culture. Bull. Exp. Biol. Med., 170(4), 528–536. DOI
  53. Longhini, A.L.F., Salazar, T.E., Vieira, C., Trinh, T., Duan, Y., Pay, L.M., Li Calzi, S., Losh, M., Johnston, N.A., Xie, H., Kim, M., Hunt, R.J., Yoder, M.C., Santoro, D., McCarrel, T.M., Grant, M.B. (2019) Peripheral blood-derived mesenchymal stem cells demonstrate immunomodulatory potential for therapeutic use in horses. PLoS One, 14(3), e0212642. DOI
  54. Uzieliene, I., Bialaglovyte, P., Miksiunas, R., Lebedis, I., Pachaleva, J., Vaiciuleviciute, R., Ramanaviciene, A., Kvederas, G., Bernotiene, E. (2023) Menstrual blood-derived stem cell paracrine factors possess stimulatory effects on chondrogenesis in vitro and diminish the degradation of articular cartilage during osteoarthritis.Bioengineering (Basel), 10(9), 1001. DOI
  55. Lupatov, A.Y., Saryglar, R.Y., Vtorushina, V.V., Poltavtseva, R.A., Bystrykh, O.A., Chuprynin, V.D., Krechetova, L.V., Pavlovich, S.V., Yarygin, K.N., Sukhikh, G.T. (2021) Mesenchymal stromal cells isolated from ectopic but not eutopic endometrium display pronounced immunomodulatory activity in vitro. Biomedicines, 9(10), 1286. DOI
  56. Vakhrushev, I.V., Antonov, E.N., Popova, A.V., Konstantinova, E.V., Karalkin, P.A., Kholodenko, I.V., Lupatov,A.Y., Popov, V.K., Bagratashvili, V.N., Yarygin, K.N. (2012) Design of tissue engineering implants for bone tissue regeneration of the basis of new generation polylactoglycolide scaffolds and multipotent mesenchymal stem cells from human exfoliated deciduous teeth (SHED cells). Bull. Exp. Biol. Med., 153(1), 143–147. DOI
  57. Burunova, V.V., Gisina, A.M., Kholodenko, I.V., Lupatov, A.Y., Shragina, O.A., Yarygin, K.N. (2010) Standardization of biochemical profile of mesenchymal cell materials by probing the level of dehydrogenase activity. Bull. Exp. Biol. Med., 149(4), 497–501. DOI
  58. Miceli, V., Bulati, M., Iannolo, G., Zito, G., Gallo, A., Conaldi, P.G. (2021) Therapeutic properties of mesenchymal stromal/stem cells: The need of cell priming for cell-free therapies in regenerative medicine. Int. J. Mol. Sci., 22(2), 763. DOI
  59. Lotfy, A., AboQuella, N.M., Wang, H. (2023) Mesenchymal stromal/stem cell (MSC)-derived exosomes in clinical trials. Stem Cell Res. Ther., 14(1), 66. DOI
  60. Krampera, M., le Blanc, K. (2021) Mesenchymal stromal cells: Putative microenvironmental modulators become cell therapy. Cell Stem Cell, 28(10), 1708–1725. DOI
  61. Yarygin, K.N., Namestnikova, D.D., Sukhinich, K.K., Gubskiy, I.L., Majouga, A.G., Kholodenko, I.V. (2021) Cell therapy of stroke: Do the intra-arterially transplanted mesenchymal stem cells cross the blood-brain barrier? Cells, 10(11), 2997. DOI
  62. Kholodenko, I.V., Yarygin, K.N., Gubsky, L.V., Konieva, A.A., Tairova, R.T., Povarova, O.V., Kholodenko, R.V., Burunova, V.V., Yarygin, V.N., Skvortsova, V.I. (2012) Intravenous xenotransplantation of human placental mesenchymal stem cells to rats: Comparative analysis of homing in rat brain in two models of experimental ischemic stroke. Bull. Exp. Biol. Med., 154(1), 118–123. DOI
  63. Giovannelli, L., Bari, E., Jommi, C., Tartara, F., Armocida, D., Garbossa, D., Cofano, F., Torre, M.L., Segale, L. (2023) Mesenchymal stem cell secretome and extracellular vesicles for neurodegenerative diseases: Risk-benefit profile and next steps for the market access. Bioact. Mater., 29, 16–35. DOI
  64. Xu, F., Fei, Z., Dai, H., Xu, J., Fan, Q., Shen, S., Zhang, Y., Ma, Q., Chu, J., Peng, F., Zhou, F., Liu, Z., Wang, C. (2022) Mesenchymal stem cell-derived extracellular vesicles with high PD-L1 expression for autoimmune diseases treatment. Adv. Mater., 34(1), e2106265. DOI
  65. Liu, H., Li, R., Liu, T., Yang, L., Yin, G., Xie, Q. (2020) Immunomodulatory effects of mesenchymal stem cells and mesenchymal stem cell-derived extracellular vesicles in rheumatoid arthritis. Front. Immunol., 11, 1912. DOI
  66. Kholodenko, I.V., Kholodenko, R.V., Yarygin, K.N. (2023) The crosstalk between mesenchymal stromal/stem cells and hepatocytes in homeostasis and under stress. Int. J. Mol. Sci., 24(20), 15212. DOI
  67. Kholodenko, I.V., Kholodenko, R.V., Lupatov, A.Y., Yarygin, K.N. (2018) Cell therapy as a tool for induction of immunological tolerance after liver transplantation. Bull. Exp. Biol. Med., 165(4), 554–563. DOI
  68. Soontararak, S., Chow, L., Johnson, V., Coy, J., Wheat, W., Regan, D., Dow, S. (2018) Mesenchymal Stem Cells (MSC) derived from induced pluripotent stem cells (iPSC) equivalent to adipose-derived MSC in promoting intestinal healing and microbiome normalization in mouse inflammatory bowel disease model. Stem Cells Transl. Med., 7(6), 456–467. DOI
  69. Gnecchi, M., Danieli, P., Malpasso, G., Ciuffreda, M.C. (2016) Paracrine mechanisms of mesenchymal stem cells in tissue repair. Methods Mol. Biol., 1416, 123–146. DOI
  70. Eggenhofer, E., Luk, F., Dahlke, M.H., Hoogduijn, M.J. (2014) The life and fate of mesenchymal stem cells. Front. Immunol., 5, 148. DOI
  71. Pang, S.H.M., d'Rozario, J., Mendonca, S., Bhuvan, T., Payne, N.L., Zheng, D., Hisana, A., Wallis, G., Barugahare, A., Powell, D., Rautela, J., Huntington, N.D., Dewson, G., Huang, D.C.S., Gray, D.H.D., Heng, T.S.P. (2021) Mesenchymal stromal cell apoptosis is required for their therapeutic function. Nat. Commun., 12(1), 6495. DOI
  72. Preda, M.B., Lupan, A.M., Neculachi, C.A., Leti, L.I., Fenyo, I.M., Popescu, S., Rusu, E.G., Marinescu, C.I., Simionescu, M., Burlacu, A. (2020) Evidence of mesenchymal stromal cell adaptation to local microenvironment following subcutaneous transplantation. J. Cell. Mol. Med., 24(18), 10889–10897. DOI
  73. Li, X., Jiang, Y., Liu, X., Fu, J., Du, J., Luo, Z., Xu, J., Bhawal, U.K., Liu, Y., Guo, L. (2023) Mesenchymal stem cell-derived apoptotic bodies alleviate alveolar bone destruction by regulating osteoclast differentiation and function. Int. J. Oral Sci., 15(1), 51. DOI
  74. Zhu, W., Chen, J., Cong, X., Hu, S., Chen, X. (2006) Hypoxia and serum deprivation-induced apoptosis in mesenchymal stem cells. Stem Cells, 24(2), 416–245. DOI
  75. Galleu, A., Riffo-Vasquez, Y., Trento, C., Lomas, C., Dolcetti, L., Cheung, T.S., von Bonin, M., Barbieri, L., Halai, K., Ward, S., Weng, L., Chakraverty, R., Lombardi, G., Watt, F.M., Orchard, K., Marks, D.I., Apperley, J., Bornhauser, M., Walczak, H., Bennett, C., Dazzi, F. (2017) Apoptosis in mesenchymal stromal cells induces in vivo recipient-mediated immunomodulation. Sci. Transl. Med., 9(416), eaam7828. DOI
  76. Yamaza, T., Miura, Y., Bi, Y., Liu, Y., Akiyama, K., Sonoyama, W., Patel, V., Gutkind, S., Young, M., Gronthos, S., Le, A., Wang, C.Y., Chen, W., Shi, S. (2008) Pharmacologic stem cell based intervention as a new approach to osteoporosis treatment in rodents. PLoS ONE, 3(7), e2615. DOI
  77. Ham, O., Lee, S.Y., Song, B.W., Cha, M.J., Lee, C.Y., Park, J.H., Kim, I.K., Lee, J., Seo, H.H., Seung, M.J., Choi, E., Jang, Y., Hwang, K.C. (2015) Modulation of Fas-Fas ligand interaction rehabilitates hypoxia-induced apoptosis of mesenchymal stem cells in ischemic myocardium niche. Cell Transplant., 24(7), 1329–1341. DOI
  78. Kennea, N.L., Stratou, C., Naparus,A., Fisk, N.M., Mehmet,H. (2005) Functional intrinsic and extrinsic apoptotic pathways in human fetal mesenchymal stem cells. Cell Death Differ., 12(11), 1439–1441. DOI
  79. Manns, J., Daubrawa, M., Driessen, S., Paasch, F., Hoffmann, N., Löffler, A., Lauber, K., Dieterle, A., Alers, S., Iftner, T., Schulze-Osthoff, K., Stork, B., Wesselborg, S. (2011) Triggering of a novel intrinsic apoptosis pathway by the kinase inhibitor staurosporine: Activation of caspase-9 in the absence of Apaf-1. FASEB J., 25(9), 3250–3261. DOI
  80. Götherström, C., Lundqvist, A., Duprez, I.R., Childs, R., Berg, L., le Blanc, K. (2011) Fetal and adult multipotent mesenchymal stromal cells are killed by different pathways. Cytotherapy, 13(3), 269–278. DOI
  81. Kholodenko, I.V., Gisina, A.M., Manukyan, G.V., Majouga, A.G., Svirshchevskaya, E.V., Kholodenko, R.V., Yarygin, K.N. (2022) Resistance of human liver mesenchymal stem cells to FAS-induced cell death. Curr. Issues Mol. Biol., 44(8), 3428–3443. DOI
  82. Rodrigues, M., Turner, O., Stolz, D., Griffith, L.G., Wells, A. (2012) Production of reactive oxygen species by multipotent stromal cells/mesenchymal stem cells upon exposure to Fas ligand. Cell Transplant., 21(10), 2171–2187. DOI
  83. Solodeev, I., Meilik, B., Volovitz, I., Sela, M., Manheim, S., Yarkoni, S., Zipori, D., Gur, E., Shani, N. (2018) Fas-L promotes the stem cell potency of adipose-derived mesenchymal cells. Cell Death Dis., 9(6), 695. DOI
  84. Szegezdi, E., O'Reilly, A., Davy, Y., Vawda, R., Taylor, D.L., Murphy, M., Samali, A., Mehmet,H. (2009) Stem cells are resistant to TRAIL receptor-mediated apoptosis. J. Cell. Mol. Med., 13(11–12), 4409–4414. DOI
  85. Secchiero, P., Melloni, E., Corallini, F., Beltrami, A.P., Alviano, F., Milani, D., d'Aurizio, F., di Iasio, M.G., Cesselli, D., Bagnara, G.P., Zauli, G. (2008) Tumor necrosis factor-related apoptosis-inducing ligand promotes migration of human bone marrow multipotent stromal cells. Stem Cells, 26(11), 2955–2963. DOI
  86. Driscoll, P.C. (2014) Structural studies of death receptors. Methods Enzymol., 545, 201–242. DOI
  87. Mbongue, J.C., Nicholas, D.A., Torrez, T.W., Kim, N.S., Firek, A.F., Langridge, W.H. (2015) The role of indoleamine 2, 3-dioxygenase in immune suppression and autoimmunity. Vaccines (Basel), 3(3), 703–729. DOI
  88. Bikorimana, J.P., Saad, W., Abusarah, J., Lahrichi, M., Talbot, S., Shammaa, R., Rafei, M. (2022) CD146 defines a mesenchymal stromal cell subpopulation with enhanced suppressive properties. Cells, 11(15), 2263. DOI
  89. Liu, J., Qiu, X., Lv, Y., Zheng, C., Dong, Y., Dou, G., Zhu, B., Liu, A., Wang, W., Zhou, J., Liu, S., Liu, S., Gao, B., Jin, Y. (2020) Apoptotic bodies derived from mesenchymal stem cells promote cutaneous wound healing via regulating the functions of macrophages. Stem Cell Res. Ther., 11(1), 507. DOI
  90. Shapouri-Moghaddam, A., Mohammadian, S., Vazini, H., Taghadosi, M., Esmaeili, S.A., Mardani, F., Seifi, B., Mohammadi, A., Afshari, J.T., Sahebkar, A. (2018) Macrophage plasticity, polarization, and function in health and disease. J. Cell. Physiol., 233(9), 6425–6440. DOI
  91. Yang, Z., Ming, X.F. (2014) Functions of arginase isoforms in macrophage inflammatory responses: Impact on cardiovascular diseases and metabolic disorders. Front. Immunol., 5, 533. DOI
  92. Shevela, E.Ya., Sakhno, L.V., Maksimova, A.A., Tikhonova, M.A., Ostanin, A.A., Chernykh, E.R. (2022) Expression of Arg1 and MerTK by human macrophages activated by M2-polarizing stimuli and their role in determining low allostimulatory activity. Immunologiya, 43(5), 515–524. DOI
  93. Weigert, A., Olesch, C., Brüne, B. (2019) Sphingosine-1- phosphate and macrophage biology — how the sphinx tames the big eater. Front. Immunol., 10, 1706. DOI
  94. Weichand, B., Weis, N., Weigert, A., Grossmann, N., Levkau, B., Brüne, B. (2013) Apoptotic cells enhance sphingosine-1-phosphate receptor 1 dependent macrophage migration. Eur. J. Immunol., 43(12), 3306–3313. DOI
  95. Luo, B., Gan, W., Liu, Z., Shen, Z., Wang, J., Shi, R., Liu, Y., Liu, Y., Jiang, M., Zhang, Z., Wu, Y. (2016) Erythropoeitin signaling in macrophages promotes dying cell clearance and immune tolerance. Immunity, 44(2), 287–302. DOI
  96. de Witte, S.F.H., Luk, F., Sierra Parraga, J.M., Gargesha, M., Merino, A., Korevaar, S.S., Shankar, A.S., O'Flynn, L., Elliman, S.J., Roy, D., Betjes, M.G.H., Newsome, P.N., Baan, C.C., Hoogduijn, M.J. (2018) Immunomodulation by therapeutic mesenchymal stromal cells (MSC) is triggered through phagocytosis of MSC by monocytic cells. Stem Cells, 36(4), 602–615. DOI
  97. Cheung, T.S., Galleu, A., von Bonin, M., Bornhäuser, M., Dazzi, F. (2019) Apoptotic mesenchymal stromal cells induce prostaglandin E2 in monocytes: Implications for the monitoring of mesenchymal stromal cell activity. Haematologica, 104(10), e438–e441. DOI
  98. Wang, R., Hao, M., Kou, X., Sui, B., Sanmillan, M.L., Zhang, X., Liu, D., Tian, J., Yu, W., Chen, C., Yang, R., Sun, L., Liu, Y., Giraudo, C., Rao, D.A., Shen, N., Shi, S. (2022) Apoptotic vesicles ameliorate lupus and arthritis via phosphatidylserinemediated modulation of T cell receptor signaling. Bioact. Mater., 25, 472–484. DOI
  99. Ma, L., Chen, C., Liu, D., Huang, Z., Li, J., Liu, H., Kin Kwok, R.T., Tang, B., Sui, B., Zhang, X., Tang, J., Mao, X., Huang, W., Shi, S., Kou, X. (2022) Apoptotic extracellular vesicles are metabolized regulators nurturing the skin and hair. Bioact. Mater., 19, 626–641. DOI
  100. Liu, H., Liu, S., Qiu, X., Yang, X., Bao, L., Pu, F., Liu, X., Li, C., Xuan, K., Zhou, J., Deng, Z., Liu, S., Jin, Y. (2020) Donor MSCs release apoptotic bodies to improve myocardial infarction via autophagy regulation in recipient cells. Autophagy, 16(12), 2140–2155. DOI
  101. Li, Z., Wu, M., Liu, S., Liu, X., Huan, Y., Ye, Q., Yang, X., Guo, H., Liu, A., Huang, X., Yang, X., Ding, F., Xu, H., Zhou, J., Liu, P., Liu, S., Jin, Y., Xuan, K. (2022) Apoptotic vesicles activate autophagy in recipient cells to induce angiogenesis and dental pulp regeneration. Mol. Ther., 30(10), 3193–3208. DOI
  102. Nussenzweig, S.C., Verma, S., Finkel, T. (2015) The role of autophagy in vascular biology. Circ. Res., 116(3), 480–488. DOI
  103. Liu, D., Kou, X., Chen, C., Liu, S., Liu, Y., Yu, W., Yu, T., Yang, R., Wang, R., Zhou, Y., Shi, S. (2018) Circulating apoptotic bodies maintain mesenchymal stem cell homeostasis and ameliorate osteopenia via transferring multiple cellular factors. Cell Res., 28(9), 918–933. DOI
  104. Zheng, C., Sui, B., Zhang, X., Hu, J., Chen, J., Liu, J., Wu, D., Ye, Q., Xiang, L., Qiu, X., Liu, S., Deng, Z., Zhou, J., Liu, S., Shi, S., Jin, Y. (2021) Apoptotic vesicles restore liver macrophage homeostasis to counteract type 2 diabetes. J. Extracell. Vesicles, 10(7), e12109. DOI
  105. Li, Y.H., Shen, S., Shao, T., Jin, M.T., Fan, D.D., Lin, A.F., Xiang, L.X., Shao, J.Z. (2021) Mesenchymal stem cells attenuate liver fibrosis by targeting Ly6Chi/lo macrophages through activating the cytokine-paracrine and apoptotic pathways. Cell Death Discov., 7(1), 239. DOI