Skip to main content
SpringerLink
Log in

Secretome of Stem Cells: Roles of Extracellular Vesicles in Diseases, Stemness, Differentiation, and Reprogramming

  • Review Article
  • Published:
Tissue Engineering and Regenerative Medicine Aims and scope

Abstract

Increasing evidence suggests that stem cells or stem cell-derived cells may contribute to tissue repair, not only by replacing lost tissue but also by delivering complex sets of secretory molecules, called secretomes, into host injured tissues. In recent years, extracellular vesicles (EVs) have gained much attention for their diverse and important roles in a wide range of pathophysiological processes. EVs are released from most types of cells and mediates cell–cell communication by activating receptors on target cells or by being taken up by recipient cells. EVs, including microvesicles and exosomes, encapsulate and carry proteins, nucleic acids, and lipids in the lumen and on the cell surface. Thus, EV-mediated intercellular communication has been extensively studied across various biological processes. While a number of investigations has been conducted in different tissues and body fluids, the field lacks a systematic review on stem cell-derived EVs, especially regarding their roles in stemness and differentiation. Here, we provide an overview of the pathophysiological roles of EVs and summarize recent findings focusing on EVs released from various types of stem cells. We also highlight emerging evidence for the potential implication of EVs in self-renewal, differentiation, and reprograming and discuss the benefits and limitations in translational approaches.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data availability

The present manuscript is based on the data published and does not include original data.

References

  1. Keller G. Embryonic stem cell differentiation: emergence of a new era in biology and medicine. Genes Dev. 2005;19:1129–55.

    Article  CAS  PubMed  Google Scholar 

  2. Clarke D, Frisén J. Differentiation potential of adult stem cells. Curr Opin Genet Dev. 2001;11:575–80.

    Article  CAS  PubMed  Google Scholar 

  3. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861–72.

    Article  CAS  PubMed  Google Scholar 

  4. Volarevic V, Ljujic B, Stojkovic P, Lukic A, Arsenijevic N, Stojkovic M. Human stem cell research and regenerative medicine–present and future. Br Med Bull. 2011;99:155–68.

    Article  PubMed  Google Scholar 

  5. Choumerianou DM, Dimitriou H, Kalmanti M. Stem cells: promises versus limitations. Tissue Eng Part B Rev. 2008;14:53–60.

    Article  CAS  PubMed  Google Scholar 

  6. Baraniak PR, McDevitt TC. Stem cell paracrine actions and tissue regeneration. Regen Med. 2010;5:121–43.

    Article  PubMed  Google Scholar 

  7. Caplan AI, Dennis JE. Mesenchymal stem cells as trophic mediators. J Cell Biochem. 2006;98:1076–84.

    Article  CAS  PubMed  Google Scholar 

  8. Yang D, Wang W, Li L, Peng Y, Chen P, Huang H, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Woo DH, Kim SK, Lim HJ, Heo J, Park HS, Kang GY, et al. Direct and indirect contribution of human embryonic stem cell-derived hepatocyte-like cells to liver repair in mice. Gastroenterology. 2012;142:602–11.

    Article  CAS  PubMed  Google Scholar 

  10. An SY, Jang YJ, Lim HJ, Han J, Lee J, Lee G, et al. Milk fat globule-EGF Factor 8, secreted by mesenchymal stem cells, protects against liver fibrosis in mice. Gastroenterology. 2017;152:1174–86.

    Article  CAS  PubMed  Google Scholar 

  11. Laflamme MA, Chen KY, Naumova AV, Muskheli V, Fugate JA, Dupras SK, et al. Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat Biotechnol. 2007;25:1015–24.

    Article  CAS  PubMed  Google Scholar 

  12. Cho SW, Moon SH, Lee SH, Kang SW, Kim J, Lim JM, et al. Improvement of postnatal neovascularization by human embryonic stem cell derived endothelial-like cell transplantation in a mouse model of hindlimb ischemia. Circulation. 2007;116:2409–19.

    Article  CAS  PubMed  Google Scholar 

  13. Han C, Sun X, Liu L, Jiang H, Shen Y, Xu X, et al. Exosomes and their therapeutic potentials of stem cells. Stem Cells Int. 2016;2016:7653489.

    Article  PubMed  Google Scholar 

  14. Xia J, Minamino S, Kuwabara K, Arai S. Stem cell secretome as a new booster for regenerative medicine. Biosci Trends. 2019;13:299–307.

    Article  CAS  PubMed  Google Scholar 

  15. Öztürk S, Elçin AE, Koca A, Elçin YM. Therapeutic applications of stem cells and extracellular vesicles in emergency care: futuristic perspectives. Stem Cell Rev Rep. 2021;17:390–410.

    Article  PubMed  Google Scholar 

  16. Théry C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles. 2018;7:1535750.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Rashed MH, Bayraktar E, Helal GK, Abd-Ellah MF, Amero P, Chavez-Reyes A, et al. Exosomes: from garbage bins to promising therapeutic targets. Int J Mol Sci. 2017;18:538.

    Article  Google Scholar 

  18. Hessvik NP, Llorente A. Current knowledge on exosome biogenesis and release. Cell Mol Life Sci. 2018;75:193–208.

    Article  CAS  PubMed  Google Scholar 

  19. Akers JC, Gonda D, Kim R, Carter BS, Chen CC. Biogenesis of extracellular vesicles (EV): exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies. J Neurooncol. 2013;113:1–11.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Vlachakis D, Mitsis T, Nicolaides N, Efthimiadou A, Giannakakis A, Bacopoulou F, et al. Functions, pathophysiology and current insights of exosomal endocrinology (Review). Mol Med Rep. 2021;23:26.

    CAS  PubMed  Google Scholar 

  21. Zhang HG, Grizzle WE. Exosomes: a novel pathway of local and distant intercellular communication that facilitates the growth and metastasis of neoplastic lesions. Am J Pathol. 2014;184:28–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Matsumoto J, Stewart T, Sheng L, Li N, Bullock K, Song N, et al. Transmission of alpha-synuclein-containing erythrocyte-derived extracellular vesicles across the blood-brain barrier via adsorptive mediated transcytosis: another mechanism for initiation and progression of Parkinson’s disease? Acta Neuropathol Commun. 2017;5:71.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Farooqi AA, Desai NN, Qureshi MZ, Librelotto DRN, Gasparri ML, Bishayee A, et al. Exosome biogenesis, bioactivities and functions as new delivery systems of natural compounds. Biotechnol Adv. 2018;36:328–34.

    Article  CAS  PubMed  Google Scholar 

  24. Théry C, Duban L, Segura E, Véron P, Lantz O, Amigorena S. Indirect activation of naive CD4+ T cells by dendritic cell-derived exosomes. Nat Immunol. 2002;3:1156–62.

    Article  PubMed  Google Scholar 

  25. Skog J, Wurdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol. 2008;10:1470–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gong M, Yu B, Wang J, Wang Y, Liu M, Paul C, et al. Mesenchymal stem cells release exosomes that transfer miRNAs to endothelial cells and promote angiogenesis. Oncotarget. 2017;8:45200–12.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Gurunathan S, Kang MH, Jeyaraj M, Qasim M, Kim JH. Review of the isolation, characterization, biological function, and multifarious therapeutic approaches of exosomes. Cells. 2019;8:307.

    Article  CAS  PubMed Central  Google Scholar 

  28. Cheng L, Wang Y, Huang L. Exosomes from M1-polarized macrophages potentiate the cancer vaccine by creating a pro-inflammatory microenvironment in the lymph node. Mol Ther. 2017;25:1665–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Segura E, Nicco C, Lombard B, Véron P, Raposo G, Batteux F, et al. ICAM-1 on exosomes from mature dendritic cells is critical for efficient naive T-cell priming. Blood. 2005;106:216–23.

    Article  CAS  PubMed  Google Scholar 

  30. Gasser O, Schifferli JA. Activated polymorphonuclear neutrophils disseminate anti-inflammatory microparticles by ectocytosis. Blood. 2004;104:2543–8.

    Article  CAS  PubMed  Google Scholar 

  31. Zhu D, Tian J, Wu X, Li M, Tang X, Rui K, et al. G-MDSC-derived exosomes attenuate collagen-induced arthritis by impairing Th1 and Th17 cell responses. Biochim Biophys Acta Mol Basis Dis. 2019;1865:165540.

    Article  CAS  PubMed  Google Scholar 

  32. Pan Y, Hui X, Hoo RLC, Ye D, Chan CYC, Feng T, et al. Adipocyte-secreted exosomal microRNA-34a inhibits M2 macrophage polarization to promote obesity-induced adipose inflammation. J Clin Invest. 2019;129:834–49.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Okoye IS, Coomes SM, Pelly VS, Czieso S, Papayannopoulos V, Tolmachova T, et al. MicroRNA-containing T-regulatory-cell-derived exosomes suppress pathogenic T helper 1 cells. Immunity. 2014;41:89–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. D’Anca M, Fenoglio C, Serpente M, Arosio B, Cesari M, Scarpini EA, et al. Exosome determinants of physiological aging and age-related neurodegenerative diseases. Front Aging Neurosci. 2019;11:232.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Olivieri F, Albertini MC, Orciani M, Ceka A, Cricca M, Procopio AD, et al. DNA damage response (DDR) and senescence: shuttled inflamma-miRNAs on the stage of inflamm-aging. Oncotarget. 2015;6:35509–21.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Alique M, Ruíz-Torres MP, Bodega G, Noci MV, Troyano N, Bohórquez L, et al. Microvesicles from the plasma of elderly subjects and from senescent endothelial cells promote vascular calcification. Aging (Albany NY). 2017;9:778–89.

    Article  CAS  Google Scholar 

  37. Davis C, Dukes A, Drewry M, Helwa I, Johnson MH, Isales CM, et al. MicroRNA-183-5p Increases with Age in Bone-Derived Extracellular Vesicles, Suppresses Bone Marrow Stromal (Stem) Cell Proliferation, and Induces Stem Cell Senescence. Tissue Eng Part A. 2017;23:1231–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wang W, Wang L, Ruan L, Oh J, Dong X, Zhuge Q, et al. Extracellular vesicles extracted from young donor serum attenuate inflammaging via partially rejuvenating aged T-cell immunotolerance. FASEB J. 2018;32:fj201800059R.

    Google Scholar 

  39. Lei Q, Gao F, Liu T, Ren W, Chen L, Cao Y, et al. Extracellular vesicles deposit PCNA to rejuvenate aged bone marrow-derived mesenchymal stem cells and slow age-related degeneration. Sci Transl Med. 2021;13:eaaz8697.

    Article  CAS  PubMed  Google Scholar 

  40. Dickens AM, Tovar-Y-Romo LB, Yoo SW, Trout AL, Bae M, Kanmogne M, et al. Astrocyte-shed extracellular vesicles regulate the peripheral leukocyte response to inflammatory brain lesions. Sci Signal. 2017;10:eaai7696.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Eitan E, Hutchison ER, Marosi K, Comotto J, Mustapic M, Nigam SM, et al. Extracellular vesicle-associated Abeta mediates trans-neuronal bioenergetic and Ca(2+)-handling deficits in Alzheimer's disease models. NPJ Aging Mech Dis. 2016;2:16019.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Saman S, Kim W, Raya M, Visnick Y, Miro S, Saman S, et al. Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease. J Biol Chem. 2012;287:3842–9.

    Article  CAS  PubMed  Google Scholar 

  43. Guo Q, Furuta K, Lucien F, Gutierrez Sanchez LH, Hirsova P, Krishnan A, et al. Integrin beta1-enriched extracellular vesicles mediate monocyte adhesion and promote liver inflammation in murine NASH. J Hepatol. 2019;71:1193–205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Povero D, Panera N, Eguchi A, Johnson CD, Papouchado BG, de Araujo HL, et al. Lipid-induced hepatocyte-derived extracellular vesicles regulate hepatic stellate cell via microRNAs targeting PPAR-gamma. Cell Mol Gastroenterol Hepatol. 2015;1:646–63.e4.

    Google Scholar 

  45. Lee YS, Kim SY, Ko E, Lee JH, Yi HS, Yoo YJ, et al. Exosomes derived from palmitic acid-treated hepatocytes induce fibrotic activation of hepatic stellate cells. Sci Rep. 2017;7:3710.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Withrow J, Murphy C, Liu Y, Hunter M, Fulzele S, Hamrick MW. Extracellular vesicles in the pathogenesis of rheumatoid arthritis and osteoarthritis. Arthritis Res Ther. 2016;18:286.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Hafiane A, Daskalopoulou SS. Extracellular vesicles characteristics and emerging roles in atherosclerotic cardiovascular disease. Metabolism. 2018;85:213–22.

    Article  CAS  PubMed  Google Scholar 

  48. Kang X, Zuo Z, Hong W, Tang H, Geng W. Progress of research on exosomes in the protection against ischemic brain injury. Front Neurosci. 2019;13:1149.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Bjørge IM, Kim SY, Mano JF, Kalionis B, Chrzanowski W. Extracellular vesicles, exosomes and shedding vesicles in regenerative medicine—a new paradigm for tissue repair. Biomater Sci. 2017;6:60–78.

    Article  PubMed  Google Scholar 

  50. Szabo G, Momen-Heravi F. Extracellular vesicles in liver disease and potential as biomarkers and therapeutic targets. Nat Rev Gastroenterol Hepatol. 2017;14:455–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Al-Nedawi K, Meehan B, Micallef J, Lhotak V, May L, Guha A, et al. Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat Cell Biol. 2008;10:619–24.

    Article  CAS  PubMed  Google Scholar 

  52. Lee TH, Chennakrishnaiah S, Audemard E, Montermini L, Meehan B, Rak J. Oncogenic ras-driven cancer cell vesiculation leads to emission of double-stranded DNA capable of interacting with target cells. Biochem Biophys Res Commun. 2014;451:295–301.

    Article  CAS  PubMed  Google Scholar 

  53. Cai J, Wu G, Tan X, Han Y, Chen C, Li C, et al. Transferred BCR/ABL DNA from K562 extracellular vesicles causes chronic myeloid leukemia in immunodeficient mice. PLoS One. 2014;9:e105200.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Dinh NTH, Lee J, Lee J, Kim SS, Go G, Bae S, et al. Indoor dust extracellular vesicles promote cancer lung metastasis by inducing tumour necrosis factor-alpha. J Extracell Vesicles. 2020;9:1766821.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Wolfers J, Lozier A, Raposo G, Regnault A, Théry C, Masurier C, et al. Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming. Nat Med. 2001;7:297–303.

    Article  CAS  PubMed  Google Scholar 

  56. Lim W, Kim HS. Exosomes as therapeutic vehicles for cancer. Tissue Eng Regen Med. 2019;16:213–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ratajczak J, Miekus K, Kucia M, Zhang J, Reca R, Dvorak P, et al. Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia. 2006;20:847–56.

    Article  CAS  PubMed  Google Scholar 

  58. Tavakoli Dargani Z, Singla DK. Embryonic stem cell-derived exosomes inhibit doxorubicin-induced TLR4-NLRP3-mediated cell death-pyroptosis. Am J Physiol Heart Circ Physiol. 2019;317:H460–71.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Chen B, Sun Y, Zhang J, Zhu Q, Yang Y, Niu X, et al. Human embryonic stem cell-derived exosomes promote pressure ulcer healing in aged mice by rejuvenating senescent endothelial cells. Stem Cell Res Ther. 2019;10:142.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Zhang Y, Kim MS, Jia B, Yan J, Zuniga-Hertz JP, Han C, et al. Hypothalamic stem cells control ageing speed partly through exosomal miRNAs. Nature. 2017;548:52–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Zhu B, Zhang L, Liang C, Liu B, Pan X, Wang Y, et al. Stem cell-derived exosomes prevent aging-induced cardiac dysfunction through a novel exosome/lncRNA MALAT1/NF-kappaB/TNF-alpha signaling pathway. Oxid Med Cell Longev. 2019;2019:9739258.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Kulkarni R, Bajaj M, Ghode S, Jalnapurkar S, Limaye L, Kale VP. Intercellular transfer of microvesicles from young mesenchymal stromal cells rejuvenates aged murine hematopoietic stem cells. Stem Cells. 2018;36:420–33.

    Article  CAS  PubMed  Google Scholar 

  63. Gong L, Chen B, Zhang J, Sun Y, Yuan J, Niu X, et al. Human ESC-sEVs alleviate age-related bone loss by rejuvenating senescent bone marrow-derived mesenchymal stem cells. J Extracell Vesicles. 2020;9:1800971.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Liu S, Mahairaki V, Bai H, Ding Z, Li J, Witwer KW, et al. Highly purified human extracellular vesicles produced by stem cells alleviate aging cellular phenotypes of senescent human cells. Stem Cells. 2019;37:779–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Xin H, Li Y, Cui Y, Yang JJ, Zhang ZG, Chopp M. Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J Cereb Blood Flow Metab. 2013;33:1711–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Xin H, Katakowski M, Wang F, Qian JY, Liu XS, Ali MM, et al. MicroRNA cluster miR-17-92 Cluster in exosomes enhance neuroplasticity and functional recovery after stroke in rats. Stroke. 2017;48:747–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lee JY, Kim E, Choi SM, Kim DW, Kim KP, Lee I, et al. Microvesicles from brain-extract-treated mesenchymal stem cells improve neurological functions in a rat model of ischemic stroke. Sci Rep. 2016;6:33038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Webb RL, Kaiser EE, Scoville SL, Thompson TA, Fatima S, Pandya C, et al. Human neural stem cell extracellular vesicles improve tissue and functional recovery in the murine thromboembolic stroke model. Transl Stroke Res. 2018;9:530–9.

    Article  CAS  PubMed  Google Scholar 

  69. Webb RL, Kaiser EE, Jurgielewicz BJ, Spellicy S, Scoville SL, Thompson TA, et al. Human neural stem cell extracellular vesicles improve recovery in a porcine model of ischemic stroke. Stroke. 2018;49:1248–56.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Lee M, Liu T, Im W, Kim M. Exosomes from adipose-derived stem cells ameliorate phenotype of Huntington’s disease in vitro model. Eur J Neurosci. 2016;44:2114–9.

    Article  PubMed  Google Scholar 

  71. Chun C, Smith AST, Kim H, Kamenz DS, Lee JH, Lee JB, et al. Astrocyte-derived extracellular vesicles enhance the survival and electrophysiological function of human cortical neurons in vitro. Biomaterials. 2021;271:120700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Zhu YG, Feng XM, Abbott J, Fang XH, Hao Q, Monsel A, et al. Human mesenchymal stem cell microvesicles for treatment of Escherichia coli endotoxin-induced acute lung injury in mice. Stem Cells. 2014;32:116–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Monsel A, Zhu YG, Gennai S, Hao Q, Hu S, Rouby JJ, et al. Therapeutic effects of human mesenchymal stem cell-derived microvesicles in severe pneumonia in mice. Am J Respir Crit Care Med. 2015;192:324–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hao Q, Gudapati V, Monsel A, Park JH, Hu S, Kato H, et al. Mesenchymal stem cell-derived extracellular vesicles decrease lung injury in mice. J Immunol. 2019;203:1961–72.

    Article  CAS  PubMed  Google Scholar 

  75. Khatri M, Richardson LA, Meulia T. Mesenchymal stem cell-derived extracellular vesicles attenuate influenza virus-induced acute lung injury in a pig model. Stem Cell Res Ther. 2018;9:17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Bari E, Ferrarotti I, Di Silvestre D, Grisoli P, Barzon V, Balderacchi A, et al. Adipose mesenchymal extracellular vesicles as alpha-1-antitrypsin physiological delivery systems for lung regeneration. Cells. 2019;8:965.

    Article  CAS  PubMed Central  Google Scholar 

  77. Li T, Yan Y, Wang B, Qian H, Zhang X, Shen L, et al. Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis. Stem Cells Dev. 2013;22:845–54.

    Article  CAS  PubMed  Google Scholar 

  78. Qu Y, Zhang Q, Cai X, Li F, Ma Z, Xu M, et al. Exosomes derived from miR-181-5p-modified adipose-derived mesenchymal stem cells prevent liver fibrosis via autophagy activation. J Cell Mol Med. 2017;21:2491–502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Kim H, Lee MJ, Bae EH, Ryu JS, Kaur G, Kim HJ, et al. Comprehensive molecular profiles of functionally effective MSC-derived extracellular vesicles in immunomodulation. Mol Ther. 2020;28:1628–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Yao J, Zheng J, Cai J, Zeng K, Zhou C, Zhang J, et al. Extracellular vesicles derived from human umbilical cord mesenchymal stem cells alleviate rat hepatic ischemia-reperfusion injury by suppressing oxidative stress and neutrophil inflammatory response. FASEB J. 2019;33:1695–710.

    Article  CAS  PubMed  Google Scholar 

  81. Haga H, Yan IK, Borrelli DA, Matsuda A, Parasramka M, Shukla N, et al. Extracellular vesicles from bone marrow-derived mesenchymal stem cells protect against murine hepatic ischemia/reperfusion injury. Liver Transpl. 2017;23:791–803.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Rostom DM, Attia N, Khalifa HM, Abou Nazel MW, El Sabaawy EA. The therapeutic potential of extracellular vesicles versus mesenchymal stem cells in liver damage. Tissue Eng Regen Med. 2020;17:537–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Bruno S, Pasquino C, Herrera Sanchez MB, Tapparo M, Figliolini F, Grange C, et al. HLSC-Derived extracellular vesicles attenuate liver fibrosis and inflammation in a murine model of non-alcoholic steatohepatitis. Mol Ther. 2020;28:479–89.

    Article  CAS  PubMed  Google Scholar 

  84. Hyung S, Jeong J, Shin K, Kim JY, Yim JH, Yu CJ, et al. Exosomes derived from chemically induced human hepatic progenitors inhibit oxidative stress induced cell death. Biotechnol Bioeng. 2020;117:2658–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Bruno S, Grange C, Deregibus MC, Calogero RA, Saviozzi S, Collino F, et al. Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol. 2009;20:1053–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Bruno S, Grange C, Collino F, Deregibus MC, Cantaluppi V, Biancone L, et al. Microvesicles derived from mesenchymal stem cells enhance survival in a lethal model of acute kidney injury. PLoS One. 2012;7:e33115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Tomasoni S, Longaretti L, Rota C, Morigi M, Conti S, Gotti E, et al. Transfer of growth factor receptor mRNA via exosomes unravels the regenerative effect of mesenchymal stem cells. Stem Cells Dev. 2013;22:772–80.

    Article  CAS  PubMed  Google Scholar 

  88. Lin KC, Yip HK, Shao PL, Wu SC, Chen KH, Chen YT, et al. Combination of adipose-derived mesenchymal stem cells (ADMSC) and ADMSC-derived exosomes for protecting kidney from acute ischemia-reperfusion injury. Int J Cardiol. 2016;216:173–85.

    Article  PubMed  Google Scholar 

  89. Ha DH, Kim HK, Lee J, Kwon HH, Park GH, Yang SH, et al. Mesenchymal stem/stromal cell-derived exosomes for immunomodulatory therapeutics and skin regeneration. Cells. 2020;9:1157.

    Article  CAS  PubMed Central  Google Scholar 

  90. Kim M, Shin DI, Choi BH, Min BH. Exosomes from IL-1beta-primed mesenchymal stem cells inhibited IL-1beta- and TNF-alpha-mediated inflammatory responses in osteoarthritic SW982 cells. Tissue Eng Regen Med. 2021;18:525–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Heo JS, Kim S, Yang CE, Choi Y, Song SY, Kim HO. Human adipose mesenchymal stem cell-derived exosomes: a key player in wound healing. Tissue Eng Regen Med. 2021;18:537–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Kim S, Lee SK, Kim H, Kim TM. Exosomes secreted from induced pluripotent stem cell-derived mesenchymal stem cells accelerate skin cell proliferation. Int J Mol Sci. 2018;19:3119.

    Article  PubMed Central  Google Scholar 

  93. El Harane N, Kervadec A, Bellamy V, Pidial L, Neametalla HJ, Perier MC, et al. Acellular therapeutic approach for heart failure: in vitro production of extracellular vesicles from human cardiovascular progenitors. Eur Heart J. 2018;39:1835–47.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Wu Q, Wang J, Tan WLW, Jiang Y, Wang S, Li Q, et al. Extracellular vesicles from human embryonic stem cell-derived cardiovascular progenitor cells promote cardiac infarct healing through reducing cardiomyocyte death and promoting angiogenesis. Cell Death Dis. 2020;11:354.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Khan M, Nickoloff E, Abramova T, Johnson J, Verma SK, Krishnamurthy P, et al. Embryonic stem cell-derived exosomes promote endogenous repair mechanisms and enhance cardiac function following myocardial infarction. Circ Res. 2015;117:52–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Wang Y, Zhang L, Li Y, Chen L, Wang X, Guo W, et al. Exosomes/microvesicles from induced pluripotent stem cells deliver cardioprotective miRNAs and prevent cardiomyocyte apoptosis in the ischemic myocardium. Int J Cardiol. 2015;192:61–9.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Singla DK, Johnson TA, Tavakoli Dargani Z. Exosome treatment enhances anti-inflammatory M2 macrophages and reduces inflammation-induced pyroptosis in doxorubicin-induced cardiomyopathy. Cells. 2019;8:1224.

    Article  CAS  PubMed Central  Google Scholar 

  98. Adamiak M, Cheng G, Bobis-Wozowicz S, Zhao L, Kedracka-Krok S, Samanta A, et al. Induced Pluripotent Stem Cell (iPSC)-derived extracellular vesicles are safer and more effective for cardiac repair than iPSCs. Circ Res. 2018;122(2):296–309.

    Article  CAS  PubMed  Google Scholar 

  99. Povero D, Pinatel EM, Leszczynska A, Goyal NP, Nishio T, Kim J, et al. Human induced pluripotent stem cell-derived extracellular vesicles reduce hepatic stellate cell activation and liver fibrosis. JCI Insight. 2019;5:e125652.

    Article  Google Scholar 

  100. Berschneider B, Ellwanger DC, Baarsma HA, Thiel C, Shimbori C, White ES, et al. miR-92a regulates TGF-beta1-induced WISP1 expression in pulmonary fibrosis. Int J Biochem Cell Biol. 2014;53:432–41.

    Article  CAS  PubMed  Google Scholar 

  101. Collino F, Lopes JA, Tapparo M, Tortelote GG, Kasai-Brunswick TH, Lopes GMC, et al. Extracellular vesicles derived from induced pluripotent stem cells promote renoprotection in acute kidney injury model. Cells. 2020;9:453.

    Article  CAS  PubMed Central  Google Scholar 

  102. El Andaloussi S, Lakhal S, Mäger I, Wood MJ. Exosomes for targeted siRNA delivery across biological barriers. Adv Drug Deliv Rev. 2013;65:391–7.

    Article  PubMed  Google Scholar 

  103. Ju Z, Ma J, Wang C, Yu J, Qiao Y, Hei F. Exosomes from iPSCs delivering siRNA attenuate intracellular adhesion molecule-1 expression and neutrophils adhesion in pulmonary microvascular endothelial cells. Inflammation. 2017;40:486–96.

    Article  CAS  PubMed  Google Scholar 

  104. Qamar AY, Mahiddine FY, Bang S, Fang X, Shin ST, Kim MJ, et al. Extracellular vesicle mediated crosstalk between the gametes, conceptus, and female reproductive tract. Front Vet Sci. 2020;7:589117.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Saadeldin IM, Kim SJ, Choi YB, Lee BC. Improvement of cloned embryos development by co-culturing with parthenotes: a possible role of exosomes/microvesicles for embryos paracrine communication. Cell Reprogram. 2014;16:223–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Qu P, Qing S, Liu R, Qin H, Wang W, Qiao F, et al. Effects of embryo-derived exosomes on the development of bovine cloned embryos. PLoS One. 2017;12:e0174535.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Kim J, Lee J, Lee TB, Jun JH. Embryotrophic effects of extracellular vesicles derived from outgrowth embryos in pre- and peri-implantation embryonic development in mice. Mol Reprod Dev. 2019;86:187–96.

    Article  CAS  PubMed  Google Scholar 

  108. Desrochers LM, Bordeleau F, Reinhart-King CA, Cerione RA, Antonyak MA. Microvesicles provide a mechanism for intercellular communication by embryonic stem cells during embryo implantation. Nat Commun. 2016;7:11958.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Greening DW, Nguyen HP, Elgass K, Simpson RJ, Salamonsen LA. Human endometrial exosomes contain hormone-specific cargo modulating trophoblast adhesive capacity: insights into endometrial-embryo interactions. Biol Reprod. 2016;94:38.

    Article  PubMed  Google Scholar 

  110. Das M, Kale V. Extracellular vesicles: Mediators of embryo-maternal crosstalk during pregnancy and a new weapon to fight against infertility. Eur J Cell Biol. 2020;99:151125.

    Article  CAS  PubMed  Google Scholar 

  111. Sun X, Ma X, Yang X, Zhang X. Exosomes and female infertility. Curr Drug Metab. 2019;20:773–80.

    Article  CAS  PubMed  Google Scholar 

  112. Nawaz M, Fatima F, Vallabhaneni KC, Penfornis P, Valadi H, Ekström K, et al. Extracellular vesicles: evolving factors in stem cell biology. Stem Cells Int. 2016;2016:1073140.

    Article  PubMed  Google Scholar 

  113. Kumar B, Garcia M, Weng L, Jung X, Murakami JL, Hu X, et al. Acute myeloid leukemia transforms the bone marrow niche into a leukemia-permissive microenvironment through exosome secretion. Leukemia. 2018;32:575–87.

    Article  CAS  PubMed  Google Scholar 

  114. Hornick NI, Doron B, Abdelhamed S, Huan J, Harrington CA, Shen R, et al. AML suppresses hematopoiesis by releasing exosomes that contain microRNAs targeting c-MYB. Sci Signal. 2016;9:ra88.

  115. Shi XF, Wang H, Kong FX, Xu QQ, Xiao FJ, Yang YF, et al. Exosomal miR-486 regulates hypoxia-induced erythroid differentiation of erythroleukemia cells through targeting Sirt1. Exp Cell Res. 2017;351:74–81.

    Article  CAS  PubMed  Google Scholar 

  116. Stik G, Crequit S, Petit L, Durant J, Charbord P, Jaffredo T, et al. Extracellular vesicles of stromal origin target and support hematopoietic stem and progenitor cells. J Cell Biol. 2017;216:2217–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Goloviznina NA, Verghese SC, Yoon YM, Taratula O, Marks DL, Kurre P. Mesenchymal stromal cell-derived extracellular vesicles promote myeloid-biased multipotent hematopoietic progenitor expansion via toll-like receptor engagement. J Biol Chem. 2016;291:24607–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Salvucci O, Jiang K, Gasperini P, Maric D, Zhu J, Sakakibara S, et al. MicroRNA126 contributes to granulocyte colony-stimulating factor-induced hematopoietic progenitor cell mobilization by reducing the expression of vascular cell adhesion molecule 1. Haematologica. 2012;97:818–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Lozito TP, Tuan RS. Endothelial and cancer cells interact with mesenchymal stem cells via both microparticles and secreted factors. J Cell Mol Med. 2014;18:2372–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Jo W, Jeong D, Kim J, Park J. Self-Renewal of bone marrow stem cells by nanovesicles engineered from embryonic stem cells. Adv Healthc Mater. 2016;5:3148–56.

    Article  CAS  PubMed  Google Scholar 

  121. Jung YJ, Kim HK, Cho Y, Choi JS, Woo CH, Lee KS, et al. Cell reprogramming using extracellular vesicles from differentiating stem cells into white/beige adipocytes. Sci Adv. 2020;6:eaay6721.

  122. Narayanan K, Kumar S, Padmanabhan P, Gulyas B, Wan ACA, Rajendran VM. Lineage-specific exosomes could override extracellular matrix mediated human mesenchymal stem cell differentiation. Biomaterials. 2018;182:312–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Ekström K, Omar O, Granéli C, Wang X, Vazirisani F, Thomsen P. Monocyte exosomes stimulate the osteogenic gene expression of mesenchymal stem cells. PLoS One. 2013;8:e75227.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Takeda YS, Xu Q. Neuronal Differentiation of human mesenchymal stem cells using exosomes derived from differentiating neuronal cells. PLoS One. 2015;10:e0135111.

    Article  PubMed  PubMed Central  Google Scholar 

  125. Feliciano DM, Zhang S, Nasrallah CM, Lisgo SN, Bordey A. Embryonic cerebrospinal fluid nanovesicles carry evolutionarily conserved molecules and promote neural stem cell amplification. PLoS One. 2014;9:e88810.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Bátiz LF, Castro MA, Burgos PV, Velásquez ZD, Muñoz RI, Lafourcade CA, et al. Exosomes as novel regulators of adult neurogenic niches. Front Cell Neurosci. 2016;9:501.

    Article  PubMed  PubMed Central  Google Scholar 

  127. Li F, Zhang J, Liao R, Duan Y, Tao L, Xu Y, et al. Mesenchymal stem cellderived extracellular vesicles prevent neural stem cell hypoxia injury via promoting miR2103p expression. Mol Med Rep. 2020;22:3813–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Yuan A, Farber EL, Rapoport AL, Tejada D, Deniskin R, Akhmedov NB, et al. Transfer of microRNAs by embryonic stem cell microvesicles. PLoS One. 2009;4:e4722.

    Article  PubMed  PubMed Central  Google Scholar 

  129. Hur YH, Feng S, Wilson KF, Cerione RA, Antonyak MA. Embryonic stem cell-derived extracellular vesicles maintain ESC stemness by activating FAK. Dev Cell. 2021;56:277-91.e6.

    Article  Google Scholar 

  130. Liao FL, Tan L, Liu H, Wang JJ, Ma XT, Zhao B, et al. Hematopoietic stem cell-derived exosomes promote hematopoietic differentiation of mouse embryonic stem cells in vitro via inhibiting the miR126/Notch1 pathway. Acta Pharmacol Sin. 2018;39:552–60.

    Article  CAS  PubMed  Google Scholar 

  131. Katsman D, Stackpole EJ, Domin DR, Farber DB. Embryonic stem cell-derived microvesicles induce gene expression changes in Muller cells of the retina. PLoS One. 2012;7:e50417.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Wu HH, Lee OK. Exosomes from mesenchymal stem cells induce the conversion of hepatocytes into progenitor oval cells. Stem Cell Res Ther. 2017;8:117.

    Article  PubMed  PubMed Central  Google Scholar 

  133. Zhang Y, Xu J, Liu S, Lim M, Zhao S, Cui K, et al. Embryonic stem cell-derived extracellular vesicles enhance the therapeutic effect of mesenchymal stem cells. Theranostics. 2019;9:6976–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Oh M, Lee J, Kim YJ, Rhee WJ, Park JH. Exosomes derived from human induced pluripotent stem cells ameliorate the aging of skin fibroblasts. Int J Mol Sci. 2018;19:1715.

    Article  PubMed Central  Google Scholar 

  135. Deregibus MC, Cantaluppi V, Calogero R, Lo Iacono M, Tetta C, Biancone L, et al. Endothelial progenitor cell derived microvesicles activate an angiogenic program in endothelial cells by a horizontal transfer of mRNA. Blood. 2007;110:2440–8.

    Article  CAS  PubMed  Google Scholar 

  136. Urbanelli L, Buratta S, Sagini K, Ferrara G, Lanni M, Emiliani C. Exosome-based strategies for diagnosis and therapy. Recent Pat CNS Drug Discov. 2015;10:10–27.

    Article  CAS  PubMed  Google Scholar 

  137. Cha JM, Shin EK, Sung JH, Moon GJ, Kim EH, Cho YH, et al. Efficient scalable production of therapeutic microvesicles derived from human mesenchymal stem cells. Sci Rep. 2018;8:1171.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgement

This work was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korean government (MIST) (No. 2020R1A2C2006240).

Author information

Authors and Affiliations

  1. Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, 145, Anam-ro, Seongbuk-gu, West building of Life Sciences, Seoul, 02841, South Korea

    Hyo Jin Kim, Gyeongmin Kim, Jihun Lee, Youngseok Lee & Jong-Hoon Kim

Authors
  1. Hyo Jin Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gyeongmin Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jihun Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Youngseok Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jong-Hoon Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

HJK developed the conceptual framework of the review paper. HJK, GK, JL, YL performed bibliography search and wrote the manuscript including the figure and tables. JHK designed, supervised and wrote the manuscript. All authors commented on the manuscript and agreed with submission to Tissue Engineering and Regenerative Medicine.

Corresponding author

Correspondence to Jong-Hoon Kim.

Ethics declarations

Conflict of interest

The authors declare no competing financial interest.

Informed consent

None. No investigation involving participants or volunteers has been carried out in the present study.

Ethical statement

No animal or human studies were carried out by the authors. This paper has not been previously published elsewhere and is not currently being considered for publication elsewhere.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, H.J., Kim, G., Lee, J. et al. Secretome of Stem Cells: Roles of Extracellular Vesicles in Diseases, Stemness, Differentiation, and Reprogramming. Tissue Eng Regen Med 19, 19–33 (2022). https://doi.org/10.1007/s13770-021-00406-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13770-021-00406-4

Keywords

Search

Navigation