Signal transduction pathways alter the molecular cargo of extracellular vesicles: implications in regenerative medicine

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

• 1. Van Niel G, D'Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat. Rev. Mol. Cell Biol. 19, 213–228 (2018).
  Medline CASGoogle Scholar
• 2. Mathieu M, Martin-Jaular L, Lavieu G, Théry C. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat. Cell Biol. 21, 9–17 (2019).
  Medline CASGoogle Scholar
• 3. Ramos-Zaldívar HM, Polakovicova I, Salas-Huenuleo E, Corvalán AH, Kogan MJ, Yefi CP et al. Extracellular vesicles through the blood-brain barrier: a review. Fluids Barriers CNS 19, 60 (2022).
  MedlineGoogle Scholar
• 4. Salmond N, Williams KC. Isolation and characterization of extracellular vesicles for clinical applications in cancer - time for standardization? Nanoscale Adv. 3, 1830–1852 (2021).
  Medline CASGoogle Scholar
• 5. Santos P, Almeida F. Exosome-Based Vaccines: History, Current State, and Clinical Trials. Front. Immunol. 12 doi: 10.3389/FIMMU.2021.711565 (2021).
  Google Scholar
• 6. Shkair L, Garanina EE, Stott RJ, Foster TL, Rizvanov AA, Khaiboullina SF. Membrane Microvesicles as Potential Vaccine Candidates. Int. J. Mol. Sci. 22, 1–21 (2021).
  Google Scholar
• 7. Yokoi A, Ukai M, Yasui T, Inokuma Y, Hyeon-Deuk K, Matsuzaki J et al. Identifying high-grade serous ovarian carcinoma-specific extracellular vesicles by polyketone-coated nanowires. Sci. Adv. 9, eade6958 (2023).
  Medline CASGoogle Scholar
• 8. Grange C, Tritta S, Tapparo M, Cedrino M, Tetta C, Camussi G et al. Stem cell-derived extracellular vesicles inhibit and revert fibrosis progression in a mouse model of diabetic nephropathy. Sci. Rep. 9 doi: 10.1038/S41598-019-41100-9 (2019).
  MedlineGoogle Scholar
• 9. Johnson J, Shojaee M, Mitchell Crow J, Khanabdali R. From Mesenchymal Stromal Cells to Engineered Extracellular Vesicles: A New Therapeutic Paradigm. Front. Cell. Dev. Biol. 9, 705676 (2021).
  MedlineGoogle Scholar
• 10. Knight R, Board-Davies E, Brown H, Clayton A, Davis T, Karatas B et al. Oral Progenitor Cell Line-Derived Small Extracellular Vesicles as a Treatment for Preferential Wound Healing Outcome. Stem Cells Transl. Med. 11, 861–875 (2022).
  MedlineGoogle Scholar
• 11. Nataliya B, Mikhail A, Vladimir P, Olga G, Maksim V, Ivan Z et al. Mesenchymal stromal cells facilitate resolution of pulmonary fibrosis by miR-29c and miR-129 intercellular transfer. Exp. Mol. Med. 55 doi: 10.1038/S12276-023-01017-W (2023).
  MedlineGoogle Scholar
• 12. Leidal AM, Debnath J. Unraveling the mechanisms that specify molecules for secretion in extracellular vesicles. Methods 177, 15–26 (2020).
  Medline CASGoogle Scholar
• 13. García-Silva S, Benito-Martín A, Nogués L, Hernández-Barranco A, Mazariegos MS, Santos V et al. Melanoma-derived small extracellular vesicles induce lymphangiogenesis and metastasis through an NGFR-dependent mechanism. Nat Cancer 2, 1387–1405 (2021).
  Medline CASGoogle Scholar
• 14. Cheng K, Zhao R, Li Y, Qi Y, Wang Y, Zhang Y et al. Bioengineered bacteria-derived outer membrane vesicles as a versatile antigen display platform for tumor vaccination via Plug-and-Display technology. Nat. Commun. 12 doi: 10.1038/S41467-021-22308-8 (2021).
  MedlineGoogle Scholar
• 15. Martins‐Marques T, Costa MC, Catarino S, Simoes I, Aasen T, Enguita FJ et al. Cx43-mediated sorting of miRNAs into extracellular vesicles. EMBO Rep. 23 doi: 10.15252/EMBR.202154312 (2022).
  Google Scholar
• 16. Chen Y, Zhao Y, Yin Y, Jia X, Mao L. Mechanism of cargo sorting into small extracellular vesicles. Bioengineered 12, 8186–8201 (2021).
  Medline CASGoogle Scholar
• 17. Budgude P, Kale V, Vaidya A. Pharmacological Inhibition of p38 MAPK Rejuvenates Bone Marrow Derived-Mesenchymal Stromal Cells and Boosts their Hematopoietic Stem Cell-Supportive Ability. Stem Cell Rev. Rep. 17, 2210–2222 (2021).
  Medline CASGoogle Scholar
• 18. Pendse S, Kale V, Vaidya A. The Intercellular Communication Between Mesenchymal Stromal Cells and Hematopoietic Stem Cells Critically Depends on NF-κB Signalling in the Mesenchymal Stromal Cells. Stem Cell Rev. Rep. 18, 2458–2473 (2022).
  Medline CASGoogle Scholar
• 19. Sung DK, Sung SI, Ahn SY, Chang YS, Park WS. Thrombin Preconditioning Boosts Biogenesis of Extracellular Vesicles from Mesenchymal Stem Cells and Enriches Their Cargo Contents via Protease-Activated Receptor-Mediated Signaling Pathways. Int. J. Mol. Sci. 20 doi: 10.3390/IJMS20122899 (2019). •• They analyzed the cargo content of extracellular vesicles (EVs) secreted by human umbilical cord blood-derived mesenchymal stem cells (MSCs) treated with thrombin and found that thrombin increased EV production more than fivefold.
  MedlineGoogle Scholar
• 20. Madel RJ, Börger V, Dittrich R, Bremer M, Tertel T, Phuong NNT et al. Independent human mesenchymal stromal cell-derived extracellular vesicle preparations differentially attenuate symptoms in an advanced murine graft-versus-host disease model. Cytotherapy 25, 821–836 (2023).
  Medline CASGoogle Scholar
• 21. Zanotti F, Zanolla I, Trentini M, Tiengo E, Pusceddu T, Licastro D et al. Mitochondrial Metabolism and EV Cargo of Endothelial Cells Is Affected in Presence of EVs Derived from MSCs on Which HIF Is Activated. Int. J. Mol. Sci. 24 doi: 10.3390/IJMS24066002 (2023). • They showed that EVs isolated from adipose-derived stem cells primed with deferoxamine mesylate contained the miRNAs related to cell proliferation and angiogenesis.
  Google Scholar
• 22. Zhu Y, Chen X, Liao Y. Mesenchymal Stem Cells-Derived Apoptotic Extracellular Vesicles (ApoEVs): Mechanism and Application in Tissue Regeneration. Stem Cells https://doi.org/10.1093/STMCLS/SXAD046 (2023).
  Google Scholar
• 23. Liu J, Qiu X, Lv Y, Zheng C, Dong Y, Dou G et al. Apoptotic bodies derived from mesenchymal stem cells promote cutaneous wound healing via regulating the functions of macrophages. Stem Cell Res. Ther. 11 doi: 10.1186/S13287-020-02014-W (2020).
  MedlineGoogle Scholar
• 24. Bağcı C, Sever-Bahcekapili M, Belder N, Bennett APS, Erdener ŞE, Dalkara T. Overview of extracellular vesicle characterization techniques and introduction to combined reflectance and fluorescence confocal microscopy to distinguish extracellular vesicle subpopulations. Neurophotonics 9 doi: 10.1117/1.NPH.9.2.021903 (2022).
  Google Scholar
• 25. Crescitelli R, Lässer C, Lötvall J. Isolation and characterization of extracellular vesicle subpopulations from tissues. Nature Protocols 16, 1548–1580 (2021).
  Medline CASGoogle Scholar
• 26. Salmond N, Williams KC. Isolation and characterization of extracellular vesicles for clinical applications in cancer - time for standardization? Nanoscale Adv. 3, 1830–1852 (2021).
  Medline CASGoogle Scholar
• 27. Cardoso RMS, Rodrigues SC, Gomes CF, Duarte FV, Romao M, Leal EC et al. Development of an optimized and scalable method for isolation of umbilical cord blood-derived small extracellular vesicles for future clinical use. Stem Cells Transl. Med. 10, 910–921 (2021).
  Medline CASGoogle Scholar
• 28. Pachler K, Lener T, Streif D, Dunai ZA, Desgeorges A, Feichtner M et al. A Good Manufacturing Practice-grade standard protocol for exclusively human mesenchymal stromal cell-derived extracellular vesicles. Cytotherapy 19, 458–472 (2017).
  MedlineGoogle Scholar
• 29. Lötvall J, Hill AF, Hochberg F, Buzás EI, Vizio D Di, Gardiner C et al. Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles. J. Extracell. Vesicles 3 doi: 10.3402/JEV.V3.26913 (2014).
  Google Scholar
• 30. 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 7 doi: 10.1080/20013078.2018.1535750 (2018).
  Google Scholar
• 31. Théry C, Amigorena S, Raposo G, Clayton A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr. Protoc. Cell Biol. Chapter 3 doi: 10.1002/0471143030.CB0322S30 (2006).
  Google Scholar
• 32. Wang F, Cerione RA, Antonyak MA. Isolation and characterization of extracellular vesicles produced by cell lines. STAR Protoc. 2 doi: 10.1016/J.XPRO.2021.100295 (2021).
  Google Scholar
• 33. Singh S, Moirangthem RD, Vaidya A, Jalnapurkar S, Limaye L, Kale V. AKT Signaling Prevailing in Mesenchymal Stromal Cells Modulates the Functionality of Hematopoietic Stem Cells via Intercellular Communication. Stem Cells doi: 10.1002/stem.2409 (2016).
  MedlineGoogle Scholar
• 34. 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 36, 420–433 (2018).
  Medline CASGoogle Scholar
• 35. Cardoso RMS, Rodrigues SC, Gomes CF, Duarte FV, Romao M, Leal EC et al. Development of an optimized and scalable method for isolation of umbilical cord blood-derived small extracellular vesicles for future clinical use. Stem Cells Transl. Med. 10, 910–921 (2021).
  Medline CASGoogle Scholar
• 36. Ter-Ovanesyan D, Gilboa T, Budnik B, Nikitina A, Whiteman S, Lazarovits R et al. Improved isolation of extracellular vesicles by removal of both free proteins and lipoproteins n.d. Elife doi: 10.7554/eLife ( 2023).
  MedlineGoogle Scholar
• 37. Lanna A, Vaz B, D'Ambra C, Valvo S, Vuotto C, Chiurchiù V et al. An intercellular transfer of telomeres rescues T cells from senescence and promotes long-term immunological memory. Nat. Cell Biol. 24, 1461–1474 (2022).
  Medline CASGoogle Scholar
• 38. Bellotti C, Lang K, Kuplennik N, Sosnik A, Steinfeld R. High-grade extracellular vesicles preparation by combined size-exclusion and affinity chromatography. Sci. Rep. 11, 1–13 (2021).
  MedlineGoogle Scholar
• 39. Lee JY, Kim HS. Extracellular Vesicles in Regenerative Medicine: Potentials and Challenges. Tissue Eng. Regen. Med. 18, 479–484 (2021).
  MedlineGoogle Scholar
• 40. Jin Y, Ma L, Zhang W, Yang W, Feng Q, Wang H. Extracellular signals regulate the biogenesis of extracellular vesicles. Biol. Res. 55, 1–16 (2022).
  MedlineGoogle Scholar
• 41. Wang J, Silva M, Haas LA, Morsci NS, Nguyen KCQ, Hall DH et al. C. elegans ciliated sensory neurons release extracellular vesicles that function in animal communication. Curr. Biol. 24, 519–525 (2014). • They reported that regulation of p38 MAPK pmk-1 is required for EV biogenesis in the neurons isolated from adult Caenorhabditis elegans.
  Medline CASGoogle Scholar
• 42. Datta A, Kim H, Lal M, McGee L, Johnson A, Moustafa AA et al. Manumycin A suppresses exosome biogenesis and secretion via targeted inhibition of Ras/Raf/ERK1/2 signaling and hnRNP H1 in castration-resistant prostate cancer cells. Cancer Lett. 408 doi: 10.1016/j.canlet.2017.08.020 (2017). •• They have shown that the inhibition of the ERK 1/2 signaling pathway inhibits the production of EVs in prostate cancer cells, and sensitizes them to castration. These data demonstrate the importance of studying signal transduction pathways in the regulation of EV biogenesis in cancer cells.
  Google Scholar
• 43. Di Vizio D, Morello M, Dudley AC, Schow PW, Adam RM, Morley S et al. Large oncosomes in human prostate cancer tissues and in the circulation of mice with metastatic disease. Am. J. Pathol. 181 doi: 10.1016/j.ajpath.2012.07.030 (2012).
  Google Scholar
• 44. Kim J, Morley S, Le M, Bedoret D, Umetsu DT, Di Vizio D et al. Enhanced shedding of extracellular vesicles from amoeboid prostate cancer cells. Cancer Biol. Ther. 15 doi: 10.4161/cbt.27627 (2014). •• They showed that inhibition of p38-MAPK and activation of ERK1/2 triggered the release of nano-sized extracellular vesicles in the prostate cancer cells. They also showed that the release of EVs from cancer cells suppressed the proliferation of immune cells. This study underscores the role of cancerous EVs in immune suppression.
  Google Scholar
• 45. Catalano M, O'Driscoll L. Inhibiting extracellular vesicles formation and release: a review of EV inhibitors. J. Extracell. Vesicles 9 doi: 10.1080/20013078.2019.1703244 (2019).
  Google Scholar
• 46. Szostak N, Royo F, Rybarczyk A, Szachniuk M, Blazewicz J, Del Sol A et al. Sorting signal targeting mRNA into hepatic extracellular vesicles. RNA Biol. 11, 836–844 (2014).
  MedlineGoogle Scholar
• 47. Kale VP. Application of “primed” Mesenchymal Stromal Cells in Hematopoietic Stem Cell Transplantation: Current Status and Future Prospects. Stem Cells Dev. 28, 1473–1479 (2019).
  MedlineGoogle Scholar
• 48. Li SR, Man QW, Gao X, Lin H, Wang J, Su FC et al. Tissue-derived extracellular vesicles in cancers and non-cancer diseases: present and future. J. Extracell. Vesicles 10, e12175 (2021).
  Medline CASGoogle Scholar
• 49. Son JP, Kim EH, Shin EK, Kim DH, Sung JH, Oh MJ et al. Mesenchymal Stem Cell-Extracellular Vesicle Therapy for Stroke: Scalable Production and Imaging Biomarker Studies. Stem Cells Transl. Med. 12 doi: 10.1093/STCLTM/SZAD034 (2023).
  Google Scholar
• 50. Yan D, Cao G, Mao S, Shang Z, Li C, Zhou G et al. Octopus -inspired gelatin-methacrylate scaffolds loaded with hBMSC-derived exosomes promote wound healing by regulating macrophage polarization. Smart Mater. Med. 5, 52–65 (2024).
  Google Scholar
• 51. Park DJ, Park JE, Kong TH, Seo YJ. Alteration of payload in extracellular vesicles by crosstalk with mesenchymal stem cells from different origin. J. Nanobiotechnol. 19 doi: 10.1186/S12951-021-00890-9 (2021). • They showed that EVs derived from MSCs isolated from different sources exhibit different payloads depending on the cross-talk with the recipient cells.
  MedlineGoogle Scholar
• 52. Crum RJ, Capella-Monsonís H, Badylak SF, Hussey GS. Extracellular Vesicles for Regenerative Medicine Applications. Applied Sci. 12, 7472 (2022).
  CASGoogle Scholar
• 53. Jalnapurkar S, Moirangthem RD, Singh S, Limaye L, Kale V. Microvesicles Secreted by Nitric Oxide-Primed Mesenchymal Stromal Cells Boost the Engraftment Potential of Hematopoietic Stem Cells. Stem Cells 37, 128–138 (2019). • They found that MVs derived from MSCs primed with nitric oxide are enriched in mRNAs encoding HSC-supportive genes like Jagged-1 and Vegf-A, which when cocultured with HSCs improved their engraftment ability.
  Medline CASGoogle Scholar
• 54. Sever R, Brugge JS. Signal transduction in cancer. Cold Spring. Harb. Perspect. Med. 5 doi: 10.1101/CSHPERSPECT.A006098 (2015).
  Google Scholar
• 55. Bebelman MP, Janssen E, Pegtel DM, Crudden C. The forces driving cancer extracellular vesicle secretion. Neoplasia (United States) 23, 149–157 (2021).
  Medline CASGoogle Scholar
• 56. Kalluri R. The biology and function of exosomes in cancer. J. Clin. Invest. 126, 1208–1215 (2016).
  MedlineGoogle Scholar
• 57. Bebelman MP, Smit MJ, Pegtel DM, Baglio SR. Biogenesis and function of extracellular vesicles in cancer. Pharmacol. Ther. 188, 1–11 (2018).
  Medline CASGoogle Scholar
• 58. Robado de Lope L, Sánchez-Herrero E, Serna-Blasco R, Provencio M, Romero A. Cancer as an infective disease: the role of EVs in tumorigenesis. Mol. Oncol. 17, 390–406 (2023).
  MedlineGoogle Scholar
• 59. Costa-Silva B, Aiello NM, Ocean AJ, Singh S, Zhang H, Thakur BK et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat. Cell. Biol. 17, 816–826 (2015).
  Medline CASGoogle Scholar
• 60. Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M et al. Tumour exosome integrins determine organotropic metastasis. Nature 527, 329–335 (2015).
  Medline CASGoogle Scholar
• 61. Giannandrea D, Citro V, Lesma E, Bignotto M, Platonova N, Chiaramonte R. Restoring Tissue Homeostasis at Metastatic Sites: A Focus on Extracellular Vesicles in Bone Metastasis. Front. Oncol. 11, 644109 (2021).
  Medline CASGoogle Scholar
• 62. Georgievski A, Michel A, Thomas C, Mlamla Z, Pais de Barros JP, Lemaire-Ewing S et al. Acute lymphoblastic leukemia-derived extracellular vesicles affect quiescence of hematopoietic stem and progenitor cells. Cell Death Dis. 13 doi: 10.1038/S41419-022-04761-5 (2022).
  Google Scholar
• 63. González-Callejo P, Gener P, Díaz-Riascos ZV, Conti S, Cámara-Sánchez P, Riera R et al. Extracellular vesicles secreted by triple-negative breast cancer stem cells trigger premetastatic niche remodeling and metastatic growth in the lungs. Int. J. Cancer 152, 2153–2165 (2023).
  Medline CASGoogle Scholar
• 64. Chulpanova DS, Pukhalskaia TV, Rizvanov AA, Solovyeva V V. Contribution of Tumor-Derived Extracellular Vesicles to Malignant Transformation of Normal Cells. Bioengineering 9 doi: 10.3390/BIOENGINEERING9060245 (2022).
  MedlineGoogle Scholar
• 65. Heidegger S, Stritzke F, Dahl S, Daßler-Plenker J, Joachim L, Buschmann D et al. Targeting nucleic acid sensors in tumor cells to reprogram biogenesis and RNA cargo of extracellular vesicles for T cell-mediated cancer immunotherapy. Cell Rep. Med. 101171 doi: 10.1016/J.XCRM.2023.101171 (2023).
  MedlineGoogle Scholar
• 66. Hikita T, Uehara R, Itoh RE, Mitani F, Miyata M, Yoshida T et al. MEK/ERK-mediated oncogenic signals promote secretion of extracellular vesicles by controlling lysosome function. Cancer Sci. 113, 1264–1276 (2022).
  Medline CASGoogle Scholar
• 67. Rodrigues-Junior DM, Tsirigoti C, Lim SK, Heldin CH, Moustakas A. Extracellular Vesicles and Transforming Growth Factor β Signaling in Cancer. Front. Cell Dev. Biol. 10 doi: 10.3389/FCELL.2022.849938 (2022). • They have reported that EVs secreted by cancer cells contain several macromolecules involved in the TGFβ1-mediated signaling pathway, which promotes cancer metastasis. This review summarizes how the cargo of cancerous EVs influences tumorigenesis, metastatic spread, immune evasion, and response to anti-cancer treatment.
  Google Scholar
• 68. Zhou T, Yuan Z, Weng J, Pei D, Du X, He C et al. Challenges and advances in clinical applications of mesenchymal stromal cells. J. Hematol. Oncol. 14 doi: 10.1186/S13045-021-01037-X (2021).
  MedlineGoogle Scholar
• 69. Gurunathan S, Kang MH, Kim JH. A Comprehensive Review on Factors Influences Biogenesis, Functions, Therapeutic and Clinical Implications of Exosomes. Int. J. Nanomed. 16, 1281–1312 (2021).
  MedlineGoogle Scholar
• 70. Murphy DE, de Jong OG, Brouwer M, Wood MJ, Lavieu G, Schiffelers RM et al. Extracellular vesicle-based therapeutics: natural versus engineered targeting and trafficking. Exp. Mol. Med. 51, 1–12 (2019).
  Medline CASGoogle Scholar
• 71. Ramos-Zaldívar HM, Polakovicova I, Salas-Huenuleo E, Corvalán AH, Kogan MJ, Yefi CP et al. Extracellular vesicles through the blood-brain barrier: a review. Fluids Barriers CNS 19 doi: 10.1186/S12987-022-00359-3 (2022).
  MedlineGoogle Scholar
• 72. Mathieu M, Martin-Jaular L, Lavieu G, Théry C. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nature Cell Biol. 21, 9–17 (2019).
  Medline CASGoogle Scholar
• 73. Ong SG, Wu JC. Exosomes as potential alternatives to stem cell therapy in mediating cardiac regeneration. Circ. Res. 117, 7–9 (2015).
  Medline CASGoogle Scholar
• 74. Klyachko NL, Arzt CJ, Li SM, Gololobova OA, Batrakova EV. Extracellular Vesicle-Based Therapeutics: Preclinical and Clinical Investigations. Pharmaceutics 12, 1–26 (2020).
  Google Scholar
• 75. Yuan F, Li YM, Wang Z. Preserving extracellular vesicles for biomedical applications: consideration of storage stability before and after isolation. Drug Deliv. 28, 1501–1509 (2021).
  Medline CASGoogle Scholar
• 76. Budgude P, Kale V, Vaidya A. Cryopreservation of mesenchymal stromal cell-derived extracellular vesicles using trehalose maintains their ability to expand hematopoietic stem cells in vitro. Cryobiology 98, 152–163 (2021).
  Medline CASGoogle Scholar