Review
Open Access
Extracellular Vesicles from human umbilical cord Mesenchymal Stem Cells: a potential delivery system for RNA interference-based therapeutics in cancer
1 Master’s Programme in Biomedical Sciences, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
2 Department of Biochemistry, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
3 Department of Anatomy, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
  • Volume
  • Citation
    Ahmad MU, Liem IK, Wanandi SI. Extracellular Vesicles from human umbilical cord Mesenchymal Stem Cells: a potential delivery system for RNA interference-based therapeutics in cancer. ExRNA 2024(3):0012, https://doi.org/10.55092/exrna20240012. 
  • DOI
    10.55092/exrna20240012
  • Copyright
    Copyright2024 by the authors. Published by ELSP.
Abstract

Stem Cell Therapy is currently being extensively investigated as a novel treatment approach in disease models and patients. Mesenchymal Stem Cells (MSCs) have garnered recognition as a promising reservoir for cancer therapy, offering potential as carriers for therapeutic compounds in cancer gene therapy initiatives. Recent research indicates that the therapeutic benefits of such approaches are driven by Extracellular Vesicles (EVs), released by cells and comprise a diverse array of biomolecules, including lipids, proteins, cytokines, messenger RNAs (mRNAs), transfer RNAs (tRNAs), micro-RNAs (miRNAs), long non-coding RNAs (lncRNAs), and mitochondrial DNA (mtDNA), which play a role in stimulating various endogenous processes in target cells or tissues. Specific types of miRNAs are commonly associated with cell adhesion, protein translation/stabilization, immune response, cell proliferation and platelet aggregation. This review delves into the intricate communication network between MSCs and cancer, with a particular focus on the involvement of MSC-derived EVs encapsulating miRNAs. Through a comprehensive survey of literature databases, we elucidate the pivotal role of miRNAs in tumor development, where they function as potent regulators of gene expression post-transcriptionally, exerting either oncogenic or tumor-suppressive effects.

Keywords

regulator; gene; expression; microRNA; cancer therapy

Preview
References
  • [1]Rosic G, Selakovic D, Omarova S. Cancer Signaling, Cell/Gene Therapy, Diagnosis and Role of Nanobiomaterials. Adv. Biol. Earth Sci. 2024, 9:11–34.
  • [2]Guan X, Pei Y, Song J. DNA-Based Nonviral Gene Therapy—Challenging but Promising. Mol. Pharmaceutics 2024, 21(2):427–453.
  • [3]Sohrabi B, Dayeri B, Zahedi E, Khoshbakht S, Nezamabadi Pour N, et al. Mesenchymal stem cell (MSC)-derived exosomes as novel vehicles for delivery of miRNAs in cancer therapy. Cancer Gene Ther. 2022, 29:1105–1116.
  • [4]Hardee CL, Arévalo-Soliz LM, Hornstein BD, Zechiedrich L. Advances in non-viral DNA vectors for gene therapy. Genes 2017, 8(2):65.
  • [5]Patil S, Gao YG, Lin X, Li Y, Dang K, et al. The development of functional non-viral vectors for gene delivery. Int. J. Mol. Sci. 2019, 20(21):5491.
  • [6]Taheri M, Tehrani HA, Dehghani S, Alibolandi M, Arefian E, et al. Nanotechnology and bioengineering approaches to improve the potency of mesenchymal stem cell as an off-the-shelf versatile tumor delivery vehicle. Med. Res. Rev. 2024, 44(4):1596–1661.
  • [7]Švajger U, Kamenšek U. Interleukins and interferons in mesenchymal stromal stem cell-based gene therapy of cancer. Cytokine Growth Factor Rev. 2024, 77:76–90.
  • [8]Colombo M, Raposo G, Théry C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu. Rev. Cell Dev. Biol. 2014, 30:255–289.
  • [9]Jothimani G, Pathak S, Dutta S, Duttaroy AK, Banerjee A. A comprehensive cancer-associated microRNA expression profiling and proteomic analysis of human umbilical cord mesenchymal stem cell-derived exosomes. Tissue Eng. Regen. Med. 2022, 19(5):1013–1031.
  • [10]Melzer C, Yang Y, Hass R. Interaction of SPM with tumor cells. Cell Commun. Signaling 2016, 14(1):1–12.
  • [11]Galland S, Stamenkovic I. Mesenchymal stromal cells in cancer: a review of their immunomodulatory functions and dual effects on tumor progression. J. Pathol. 2020, 250(5):555–572.
  • [12]Aprile D, Patrone D, Peluso G, Galderisi U. Multipotent/pluripotent stem cell populations in stromal tissues and peripheral blood: exploring diversity, potential, and therapeutic applications. Stem Cell Res. Ther. 2024, 15(1):139.
  • [13]Li Z, Hu X, Zhong JF. Mesenchymal stem cells: characteristics, function, and application. Stem Cells Int. 2019, 2019:8106818.
  • [14]Sisca S, Azizah N, Al Aldi MS. Potensial Mesenchymal stem cell-derived extracellular vesicles (MSC-EVS) sebagai terapi terbaru dalam iskemik retinal. Al Iqra Med. J. 2018, 1(2):65–73.
  • [15]Zhang CL, Huang T, Wu BL, He WX, Liu D. Stem cells in cancer therapy: opportunities and challenges. Oncotarget 2017, 8(43):75756.
  • [16]Théry C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, 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(1):1535750.
  • [17]El Andaloussi S, Mäger I, Breakefield XO, Wood MJ. Extracellular vesicles: biology and emerging therapeutic opportunities. Nat. Rev. Drug Discov. 2013, 12(5):347–357.
  • [18]Maas SLN, Breakefield XO, Weaver AM. Extracellular vesicles: unique intercellular delivery vehicles. Trends Cell Biol. 2012, 27(3):172–188.
  • [19]Lan T, Luo M, Wei X. Mesenchymal stem/stromal cells in cancer therapy. J. Hematol. Oncol. 2021, 14(1):1–16.
  • [20]Barreca MM, Cancemi P, Geraci F. Mesenchymal and Induced Pluripotent Stem Cells-Derived Extracellular Vesicles: The New Frontier For Regenerative Medicine? Cells 2020, 9(5):1163.
  • [21]Hade MD, Suire CN, Suo Z. Mesenchymal stem cell-derived exosomes: applications in regenerative medicine. Cells 2021, 10(8):1959.
  • [22]Johnstone RM, Adam M, Hammond JR, Orr L, Turbide C. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J. Biol. Chem. 1987, 262(19):9412–9420.
  • [23]Pan BT, Johnstone RM. Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell 1983, 33(3):967–978.
  • [24]Rani S, Ryan AE, Griffin MD, Ritter T. Mesenchymal stem cell-derived extracellular vesicles: toward cell-free therapeutic applications. Mol. Ther. 2015;23(5):812–823.
  • [25]Dutta S, Reamtong O, Panvongsa W, Kitdumrongthum S, Janpipatkul K, et al. Proteomics profiling of cholangiocarcinoma exosomes: A potential role of oncogenic protein transferring in cancer progression. Biochim. Biophys. Acta, Mol. Basis Dis. 2015, 1852(9):1989–1999.
  • [26]Olver C, Vidal M. Proteomic Analysis of Secreted Exosomes. Bertrand E, Faupel M, Eds. In Subcellular Proteomics: From Cell Deconstruction to System Reconstruction. Dordrecht: Springer, 2007, pp. 99–131.
  • [27]Stoorvogel W, Kleijmeer MJ, Geuze HJ, Raposo G. The biogenesis and functions of exosomes. Traffic 2002, 3(5):321–330.
  • [28]Li H, Li F. Exosomes from BM-SPMs increase the population of CSCs via transfer of miR-142-3p. Br. J. Cancer 2018, 119(6):744–755.
  • [29]Rosenberger L, Ezquer M, Lillo-Vera F, Pedraza PL, Ortúzar MI, et al. Stem cell exosomes inhibit angiogenesis and tumor growth of oral squamous cell carcinoma. Sci. Rep. 2019, 9(1):663.
  • [30]Vlassov AV, Magdaleno S, Setterquist R, Conrad R. Exosomes: current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials. Biochim. Biophys. Acta, Gen. Subj. 2012, 1820(7):940–948.
  • [31]Skog J, Würdinger T, Van Rijn S, Meijer DH, Gainche L, et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat. Cell Biol. 2008, 10(12):1470–1476.
  • [32]Yang Y, Bucan V, Baehre H, Von Der Ohe J, Otte ANNA, et al. Acquisition of new tumor cell properties by MSC-derived exosomes. Int. J. Oncol. 2015, 47(1):244–252.
  • [33]Qi J, Zhou Y, Jiao Z, Wang X, Zhao Y, et al. Exosomes derived from human bone marrow mesenchymal stem cells promote tumor growth through hedgehog signaling pathway. Cell. Physiol. Biochem. 2017, 42(6):2242–2254.
  • [34]Lin R, Wang S, Zhao RC. Exosomes from human adipose-derived mesenchymal stem cells promote migration through Wnt signaling pathway in a breast cancer cell model. Mol. Cell. Biochem. 2013, 383:13–20.
  • [35]Lee JK, Park SR, Jung BK, Jeon YK, Lee YS, et al. Exosomes derived from mesenchymal stem cells suppress angiogenesis by down-regulating VEGF expression in breast cancer cells. PloS one 2013, 8(12):e84256.
  • [36]Pakravan K, Babashah S, Sadeghizadeh M, Mowla SJ, Mossahebi-Mohammadi M, et al. MicroRNA-100 shuttled by mesenchymal stem cell-derived exosomes suppresses in vitro angiogenesis through modulating the mTOR/HIF-1α/VEGF signaling axis in breast cancer cells. Cell. Oncol. 2017, 40:457–470.
  • [37]Price C, Chen J. MicroRNAs in cancer biology and therapy: current status and perspectives. Genes Dis. 2014, 1(1):53–63.
  • [38]Goldie BJ, Dun MD, Lin M, Smith ND, Verrills NM, et al. Activity-associated miRNA are packaged in Map1b-enriched exosomes released from depolarized neurons. Nucleic Acids Res. 2014, 42(14):9195–9208.
  • [39]Megahed F, Tabll A, Atta S, Ragheb A, Smolic R, et al. MicroRNAs: Small Molecules with Significant Functions, Particularly in the Context of Viral Hepatitis B and C Infection. Medicina 2023, 59(1):173.
  • [40]Jame-Chenarboo F, Ng HH, Macdonald D, Mahal LK. High-Throughput Analysis Reveals miRNA Upregulating α-2, 6-Sialic Acid through Direct miRNA–mRNA Interactions. ACS Cent. Sci. 2022, 8(11):1527–1536.
  • [41]Feser R, Opperman RM, Maiti S, Majumder M. MicroRNAs: The Master Regulators of the Breast Cancer Tumor Microenvironment. Chakraborti S, Ed. In Handbook of Oxidative Stress in Cancer: Therapeutic Aspects. Singapore: Springer, 2022, pp. 1–23.
  • [42]Nasirishargh A, Kumar P, Ramasubramanian L, Clark K, Hao D, et al. Exosomal microRNAs from mesenchymal stem/stromal cells: Biology and applications in neuroprotection. World J. Stem Cells 2021, 13(7):776.
  • [43]Ni WJ, Leng XM. miRNA-dependent activation of mRNA translation. Microrna 2016, 5(2):83–86.
  • [44]Ferguson SW, Wang J, Lee CJ, Liu M, Neelamegham S, et al. The microRNA regulatory landscape of SPM-derived exosomes: a systems view. Sci. Rep. 2018, 8(1):1419.
  • [45]Chen TS, Lai RC, Lee MM, Choo ABH, Lee CN, et al. Mesenchymal stem cell secretes microparticles enriched in pre-microRNAs. Nucleic Acids Res. 2010, 38(1):215–224.
  • [46]Mathivanan S, Fahner CJ, Reid GE, Simpson RJ. ExoCarta 2012: database of exosomal proteins, RNA and lipids. Nucleic Acids Res. 2012, 40(D1):D1241–D1244.
  • [47]Keerthikumar S, Chisanga D, Ariyaratne D, Al Saffar H, Anand S, et al. ExoCarta: a web-based compendium of exosomal cargo. J. Mol. Biol. 2016, 428(4):688–692.
  • [48]Yin K, Wang S, Zhao RC. Exosomes from mesenchymal stem/stromal cells: a new therapeutic paradigm. Biomark. Res. 2019, 7(1):1–8.
  • [49]Asgarpour K, Shojaei Z, Amiri F, Ai J, Mahjoubin-Tehran M, et al. Exosomal microRNAs derived from mesenchymal stem cells: cell-to-cell messages. Cell Commun. Signaling. 2020, 18(1):1–16.
  • [50]Ragni E, Montemurro T, Montelatici E, Lavazza C, Viganò M, et al. Differential microRNA signature of human mesenchymal stem cells from different sources reveals an “environmental-niche memory” for bone marrow stem cells. Exp. Cell Res. 2013, 319(10):1562–1574.
  • [51]Vicinanza C, Lombardi E, Da Ros F, Marangon M, Durante C, et al. Modified mesenchymal stem cells in cancer therapy: A smart weapon requiring upgrades for wider clinical applications. World J. Stem Cells 2022, 14(1):54.
  • [52]Li Y, Deng X, Zeng X, Peng X. The role of Mir-148a in cancer. J. Cancer 2016, 7(10):1233.
  • [53]Tian Y, Wei W, Li L, Yang R. Down-regulation of miR-148a promotes metastasis by DNA methylation and is associated with prognosis of skin cancer by targeting TGIF2. Med. Sci. Monit. 2015, 21:3798.
  • [54]Li X, Jiang M, Chen D, Xu B, Wang R, et al. miR-148b-3p inhibits gastric cancer metastasis by inhibiting the Dock6/Rac1/Cdc42 axis. J. Exp. Clin. Cancer Res. 2018, 37:1–15.
  • [55]Yu L, Gui S, Liu Y, Qiu X, Zhang G, et al. Exosomes derived from microRNA-199a-overexpressing mesenchymal stem cells inhibit glioma progression by down-regulating AGAP2. Aging (Albany NY) 2019, 11(15):5300.
  • [56]Lou G, Chen L, Xia C, Wang W, Qi J, et al. MiR-199a-modified exosomes from adipose tissue-derived mesenchymal stem cells improve hepatocellular carcinoma chemosensitivity through mTOR pathway. J. Exp. Clin. Cancer Res. 2020, 39:1–9.
  • [57]Shang S, Wang J, Chen S, Tian R, Zeng H, et al. Exosomal miRNA‐1231 derived from bone marrow mesenchymal stem cells inhibits the activity of pancreatic cancer. Cancer Med. 2019, 8(18):7728–7740.
  • [58]Jia Y, Ding X, Zhou L, Zhang L, Yang X. Mesenchymal stem cells-derived exosomal microRNA-139-5p restrains tumorigenesis in bladder cancer by targeting PRC1. Oncogene 2021, 40(2):246–261.
  • [59]Fonsato V, Collino F, Herrera MB, Cavallari C, Deregibus MC, et al. Human liver stem cell-derived microvesicles inhibit hepatoma growth in SCID mice by delivering antitumor microRNAs. Stem Cells 2012, 30:1985–1998.
  • [60]Kim R, Lee S, Lee J, Kim M, Kim WJ, et al. Exosomes derived from microRNA-584 transfected mesenchymal stem cells: novel alternative therapeutic vehicles for cancer therapy. BMB Rep. 2018, 51(8):406.
  • [61]Beaulieu JF. Integrin α6β4 in colorectal cancer: expression, regulation, functional alterations and use as a biomarker. Cancers 2019, 12(1):41.
  • [62]Li T, Wan Y, Su Z, Li J, Han M, et al. Mesenchymal stem cell-derived exosomal microRNA-3940-5p inhibits colorectal cancer metastasis by targeting integrin α6. Dig. Dis. Sci. 2021, 66:1916–1927.
  • [63]Naseri Z, Oskuee RK, Jaafari MR, Forouzandeh Moghadam M. Exosome-mediated delivery of functionally active miRNA-142-3p inhibitor reduces tumorigenicity of breast cancer in vitro and in vivo. Int. J. Nanomed. 2018:7727–7747.