Effects of Secretomes on Neuroglia in Central Nervous System (CNS): A Systematic Review
Main Article Content
Abstract
Background: Glial cells or neuroglia are important non-neuronal components of the central nervous system (CNS), accounting for approximately 50% of its cellular composition. In addition, there are different types of neuroglia, including oligodendrocytes, astrocytes, and microglia, each with its distinct function. Several studies have shown that secretomes containing secretions from stem cells can modulate neuronal cells and neuroglia. Therefore, this study aimed to systematically review the effects of secretomes on neuroglia in CNS. Methods: The study used the Cochrane Handbook for Systematic Reviews and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic literature search was conducted on 11 electronic medical databases, followed by an assessment of quality and the risk of bias. Results: A total of 337 articles were obtained from the systematic literature search, with only 12 meeting the inclusion criteria. The results of the risk of bias assessment showed that most of the articles were in the low-risk category. Secretomes has been shown to exert beneficial effects on oligodendrocytes (2 studies), astrocytes (4 studies), and microglia (3 studies), with additional studies highlighting its dual impact on oligodendrocytes and astrocytes (2 studies), and one study demonstrating its therapeutic potential across all three glial cell types. Discussion: Secretomes positively modulate neuroglia because these cells contain growth factors, cytokines, chemoattractants, and extracellular vesicles, which carry microRNA and proteins. Conclusion: Secretomes had positive effects on neuroglia in CNS. Further studies are still needed to examine specific secretome components and molecular examination of neuroglia.
Downloads
Article Details
References
Allen NJ, Lyons DA. Glia as architects of central nervous system formation and function. Science. 2018;362(6411):181–185. doi: 10.1126/science.aat0473.
Rasband MN. Glial Contributions to Neural Function and Disease. Mol Cell Proteomics. 2016;15(2):355–361. doi: 10.1074/mcp.R115.053744.
Aninditha T, Harris S, Wiratman W. Buku Ajar Neurologi Edisi Kedua. 2022. Jakarta. Departemen Neurologi FK UI.
Cunningham CJ, Redondo-castro E, Allan SM. The therapeutic potential of the mesenchymal stem cell secretome in ischaemic stroke. J Cereb Blood Flow Metab. 2018;38(8):1276–1292. doi: 10.1177/0271678X18776802.
Behzadifard M, Aboutaleb N, Dolatshahi M, Khorramizadeh M. Neuroprotective Effects of Conditioned Medium of Mesenchymal Stem Cells (MSC ‑ CM ) as a Therapy for Ischemic Stroke Recovery : A Systematic Review. Neurochem Res. 2023;48(5):1280–1292. doi: 10.1007/s11064-022-03848-x.
Taei AA, Nasoohi S, Hassanzadeh G, Kadivar M, Dargahi L, Farahmandfar M. Enhancement of angiogenesis and neurogenesis by intracerebroventricular injection of secretome from human embryonic stem cell-derived mesenchymal stem cells in ischemic stroke model. Biomed Pharmacother. 2021;140:1–13. doi: 10.1016/j.biopha.2021.111709.
Chouaib B, Haack-sørensen M, Chaubron F, Cuisinier F. Towards the Standardization of Mesenchymal Stem Cell Secretome-Derived Product Manufacturing for Tissue Regeneration. Int J Mol Sci. 2023;24:1–15. doi: 10.3390/ijms241612594.
Gwam C, Mohammed N, Ma X. Stem cell secretome , regeneration, and clinical translation: a narrative review. Ann Transl Med. 2021;9(6):1–11. doi: 10.21037/atm-20-5030.
Pinho AG, Cibr JR, Silva NA, Monteiro S, Salgado J. Cell Secretome : Basic Insights and Therapeutic Opportunities for CNS Disorders. Pharmaceutical. 2020;13(31):1–18. doi: 10.3390/ph13020031.
Alwjwaj M, Kadir RRA, Bayraktutan U. The secretome of endothelial progenitor cells : a potential therapeutic strategy for ischemic stroke. Neural Regen Res. 2021;16(8):1483–1489. doi: 10.4103/1673-5374.303012.
Foo JB, Looi QH, Chong PP, Hassan NH, Yeo GEC, Ng CY, et al. Comparing the Therapeutic Potential of Stem Cells and their Secretory Products in Regenerative Medicine. Stem Cells Int. 2021;2021:1–30. doi: 10.1155/2021/2616807.
González-gonzález A, García-sánchez D, Dotta M, Rodríguez-rey JC, Pérez- FM, González-gonzález A, et al. Mesenchymal stem cells secretome: The cornerstone of cell-free regenerative medicine. World J Stem Cells. 2020;12(12):1529–1553. doi: 10.4252/wjsc.v12.i12.1529.
Lin L, Du L. The role of secreted factors in stem cells-mediated immune regulation. Cell Immunol. 2018;326:24–32. doi: 10.1016/j.cellimm.2017.07.010.
Putra A. Basic Molecular Stem Cells. 2019. Semarang. Unissula Press.
Li W, Shi L, Hu B, Hong Y, Zhang H, Li X, et al. Mesenchymal Stem Cell-Based Therapy for Stroke: Current Understanding and Challenges. Front Cell Neurosci. 2021;5(2):1–12. doi: 10.3389/fncel.2021.628940.
Salgado AJ, Fraga JS, Mesquita AR, Neves NM, Reis RL, Sousa N. Role of human umbilical cord mesenchymal progenitors conditioned media in neuronal/glial cell densities, viability, and proliferation. Stem Cells Dev. 2010;19(7):1067–1074. doi: 10.1089/scd.2009.0279.
Ribeiro CA, Salgado AJ, Fraga JS, Silva NA, Reis RL, Sousa N. The secretome of bone marrow mesenchymal stem cells-conditioned media varies with time and drives a distinct effect on mature neurons and glial cells (primary cultures). J Tissue Eng Regen Med. 2011;5:668–672. doi: 10.1002/term.
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ. 2021;372:1–9. doi: 10.1136/bmj.n71.
Higgins J, Thomas J, Chandler J, Cumpston M, Li T, Page M, et al. Cochrane handbook for systematic reviews of intervention 6.4. 2023. United Kingdom. John Wiley and Sons.
Page MJ, Moher D, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. PRISMA 2020 explanation and elaboration : updated guidance and exemplars for reporting systematic reviews. BMJ. 2021;372:1–36. doi: 10.1136/bmj.n160.
Campbell M, McKenzie JE, Sowden A, Katikireddi SV, Brennan SE, Ellis S, et al. Synthesis without meta-analysis (SWiM) in systematic reviews: Reporting guideline. BMJ. 2020;368:1–6. doi: 10.1136/bmj.l6890.
Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: A revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:1–8. doi: 10.1136/bmj.l4898.
Zakrzewski W, Dobrzynski M, Szymonowicz M, Rybak Z. Stem cells: past, present, and future. Stem Cell Res Ther. 2019;10(68):1–22. doi: 10.1541/ieejfms.128.329.
Undale A, Westendorf JJ, Yaszemski MJ, Khosla S. Mesenchymal Stem Cells for Bone Repair and Metabolic Bone Diseases. Mayo Clin Proc. 2009;84(10):893–902. doi: 10.1007/978-94-007-6716-4_13.
Li X, Zhang D, Yu Y, Wang L, Zhao M. Umbilical cord-derived mesenchymal stem cell secretome promotes skin regeneration and rejuvenation: From mechanism to therapeutics. Cell Prolif. 2024;57(4):1–16. doi: 10.1111/cpr.13586.
Han Y, Yang J, Fang J, Zhou Y, Candi E, Wang J, et al. The secretion profile of mesenchymal stem cells and potential applications in treating human diseases. Signal Transduct Target Ther. 2022;7(1):1–19. doi: 10.1038/s41392-022-00932-0.
Vizoso FJ, Eiro N, Cid S, Schneider J, Perez-fernandez R. Mesenchymal Stem Cell Secretome : Toward Cell-Free Therapeutic Strategies in Regenerative Medicine. Int J Mole. 2017;18(1852):1–24. doi: 10.3390/ijms18091852.
Pöyhönen S, Er S, Domanskyi A, Airavaara M. Effects of neurotrophic factors in glial cells in the central nervous system: Expression and properties in neurodegeneration and injury. Front Physiol. 2019;10(APR):1–20. doi: 10.3389/fphys.2019.00486.
Rhatomy S, Pawitan JA, Kurniawati T, Fiolin J, Dilogo IH. Allogeneic umbilical cord mesenchymal stem cell conditioned medium (secretome) for treating posterior cruciate ligament rupture: a prospective single-arm study. Eur J Orthop Surg Traumatol. 2023;33(3):669–675. doi: 10.1007/s00590-022-03278-z.
Katahira Y, Murakami F, Inoue S, Miyakawa S, Sakamoto E, Furusaka Y, et al. Protective effects of conditioned media of immortalized stem cells from human exfoliated deciduous teeth on pressure ulcer formation. Front Immunol. 2023;13(January):1–18. doi: 10.3389/fimmu.2022.1010700.
da Silva AV, Serrenho I, Araújo B, Carvalho AM, Baltazar G. Secretome as a Tool to Treat Neurological Conditions: Are We Ready? Int J Mol Sci. 2023;24(22):1–30. doi: 10.3390/ijms242216544.
Ferrini F, Juárez EH, Merighi A. Does mesenchymal stem cell’s secretome affect spinal sensory circuits? Implication for pain therapies. Neural Regen Res. 2025;20(1):181–183. doi: 10.4103/nrr.nrr-d-23-01967.
Székiová E, Michalová Z, Blaško J, Mucha R, Slovinská L, Kello M, et al. Characterisation of mesenchymal stem cells conditioned media obtained at different conditioning times: their effect on glial cells in in vitro scratch model. Growth Factors. 2023;41(2):57–70. doi: 10.1080/08977194.2023.2182145.
Rahman MM, Islam MR, Yamin M, Islam MM, Sarker MT, Meem AFK, et al. Emerging Role of Neuron-Glia in Neurological Disorders: At a Glance. Oxid Med Cell Longev. 2022;2022:1–27. doi: 10.1155/2022/3201644.
Chapman TW, Kamen Y, Piedra ET, Hill RA. Oligodendrocyte Maturation Alters the Cell Death Mechanisms That Cause Demyelination. J Neurosci. 2024;44(13):1–15. doi: 10.1523/JNEUROSCI.1794-23.2024.
Foerster S, Floriddia EM, van Bruggen D, Kukanja P, Hervé B, Cheng S, et al. Developmental origin of oligodendrocytes determines their function in the adult brain. Nat Neurosci. 2024;27(8):1545–1554. doi: 10.1038/s41593-024-01666-8.
Kuhn S, Gritti L, Crooks D, Dombrowski Y. Oligodendrocytes in Development, Myelin Generation and Beyond. Cells. 2019;8(1424):1–23. doi: 10.1016/j.coms.2016.10.001.
Michalski JP, Kothary R. Oligodendrocytes in a nutshell. Front Cell Neurosci. 2015;9(september):1–11. doi: 10.3389/fncel.2015.00340.
Bradl M, Lassmann H. Oligodendrocytes: Biology and pathology. Acta Neuropathol. 2010;119(1):37–53. doi: 10.1007/s00401-009-0601-5.
Otero-Ortega L, Laso-García F, Del Carmen Gómez-De Frutos M, Rodríguez-Frutos B, Pascual-Guerra J, Fuentes B, et al. White matter repair after extracellular vesicles administration in an experimental animal model of subcortical stroke. Sci Rep. 2017;7(3):1–11. doi: 10.1038/srep44433.
Xin H, Katakowski M, Wang F, Qian J-Y, Liu XS, Ali MM, et al. MiR-17-92 cluster in exosomes enhance neuroplasticity and functional recovery after stroke in rats. Stroke. 2017;48(3):747–753. doi: 10.1002/hep.30150.Ductular.
Tsai MJ, Liou DY, Chu YC, Chen Y, Huang MC, Huang WC, et al. Minocycline exhibits synergism with conditioned medium of bone marrow mesenchymal stem cells against ischemic stroke. J Tissue Eng Regen Med. 2021;15(3):279–292. doi: 10.1002/term.3171.
Escalada P, Ezkurdia A, Ramírez MJ, Solas M. Essential Role of Astrocytes in Learning and Memory. Int J Mol Sci. 2024;25(3):1–15. doi: 10.3390/ijms25031899.
Guillamón-Vivancos T, Gómez-Pinedo U, Matías-Guiu J. Astrocytes in neurodegenerative diseases (I): Function and molecular description. Neurologia. 2015;30(2):119–129. doi: 10.1016/j.nrl.2012.12.007.
Theparambil SM, Kopach O, Braga A, Nizari S, Hosford PS, Sagi-Kiss V, et al. Adenosine signalling to astrocytes coordinates brain metabolism and function. Nature. 2024;632(8023):139–146. doi: 10.1038/s41586-024-07611-w.
Valles SL, Singh SK, Campos-Campos J, Colmena C, Campo-Palacio I, Alvarez-Gamez K, et al. Functions of Astrocytes under Normal Conditions and after a Brain Disease. Int J Mol Sci. 2023;24(9). doi:10.3390/ijms24098434 doi: 10.3390/ijms24098434.
Gradisnik L, Velnar T. Astrocytes in the central nervous system and their functions in health and disease: A review. World J Clin Cases. 2023;11(15):3385–3394. doi: 10.12998/wjcc.v11.i15.3385.
Verkhratsky A, Butt A, Li B, Illes P, Zorec R, Semyanov A, et al. Astrocytes in human central nervous system diseases: a frontier for new therapies. Signal Transduct Target Ther. 2023;8(1):1–37. doi: 10.1038/s41392-023-01628-9.
Garland EF, Hartnell IJ, Boche D. Microglia and Astrocyte Function and Communication: What Do We Know in Humans? Front Neurosci. 2022;16(February):1–21. doi: 10.3389/fnins.2022.824888.
Perez-Catalan NA, Doe CQ, Ackerman SD. The role of astrocyte‐mediated plasticity in neural circuit development and function. Neural Dev. 2021;16(1):1–14. doi: 10.1186/s13064-020-00151-9.
Baez-Jurado E, Hidalgo-Lanussa O, Guio-Vega G, Ashraf GM, Echeverria V, Aliev G, et al. Conditioned Medium of Human Adipose Mesenchymal Stem Cells Increases Wound Closure and Protects Human Astrocytes Following Scratch Assay In Vitro. Mol Neurobiol. 2017;55(6):5377–5392. doi: 10.1007/s12035-017-0771-4.
Huang W, Lv B, Zeng H, Shi D, Liu Y, Chen F, et al. Paracrine Factors Secreted by MSCs Promote Astrocyte Survival Associated With GFAP Downregulation After Ischemic Stroke via p38 MAPK and JNK. J Cell Physiol. 2015;230(10):2461–2475. doi: 10.1002/jcp.24981.
Savli H, Gulkac MD, Esen N. The effect of stimulated microglia conditioned media on BDNF gene expression of striatal astrocytes: Quantification by real-time PCR. Int J Neurosci. 2004;114(12):1601–1612. doi: 10.1080/00207450490476138.
Wood CR, Juárez EH, Ferrini F, Myint P, Innes J, Lossi L, et al. Mesenchymal stem cell conditioned medium increases glial reactivity and decreases neuronal survival in spinal cord slice cultures. Biochem Biophys Reports. 2021;26(December):1–8. doi: 10.1016/j.bbrep.2021.100976.
Gao C, Jiang J, Tan Y, Chen S. Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets. Signal Transduct Target Ther. 2023;8(1):1–37. doi: 10.1038/s41392-023-01588-0.
Mendiola AS, Yan Z, Dixit K, Johnson JR, Bouhaddou M, Meyer-Franke A, et al. Defining blood-induced microglia functions in neurodegeneration through multiomic profiling. Nat Immunol. 2023;24(7):1173–1187. doi: 10.1038/s41590-023-01522-0.
Alekseeva OS, Kirik O V., Gilerovich EG, Korzhevskii DE. Microglia of the Brain: Origin, Structure, Functions. J Evol Biochem Physiol. 2019;55(4):257–268. doi: 10.1134/s002209301904001x.
Colonna M, Butovsky O. Microglia function in the central nervous system during health and neurodegeneration. Annu Rev Immunol. 2017;35:441–468. doi: 10.1146/annurev-immunol-051116-052358.
Wake H, Fields RD. Physiological Function of Microglia. Neuron Glia Biol. 2011;7(1):1–3. doi: 10.1017/S1740925X12000166.Physiological.
Hu J, Wang P, Wang Z, Xu Y, Peng W, Chen X, et al. Fibroblast-Conditioned Media Enhance the Yield of Microglia Isolated from Mixed Glial Cultures. Cell Mol Neurobiol. 2023;43(1):395–408. doi: 10.1007/s10571-022-01193-9.
Marfia G, Navone SE, Hadi LA, Paroni M, Berno V, Beretta M, et al. The Adipose Mesenchymal Stem Cell Secretome Inhibits Inflammatory Responses of Microglia: Evidence for an Involvement of Sphingosine-1-Phosphate Signalling. Stem Cells Dev. 2016;25(14):1095–1107. doi: 10.1089/scd.2015.0268.
Cuitavi J, Duart-Abadia P, Sanchez J, Sánchez-López CM, Lorente JD, Marcilla A, et al. Activated microglia secretome and proinflammatory cytokines increase neuronal mu-opioid receptor signalling and expression. Biochem Pharmacol. 2024;230:116608. doi: https://doi.org/10.1016/j.bcp.2024.116608.
Műzes G, Sipos F. Mesenchymal Stem Cell-Derived Secretome: A Potential Therapeutic Option for Autoimmune and Immune-Mediated Inflammatory Diseases. Cells. 2022;11:1–23. doi: 10.3390/cells11152300.