Skip to main content Skip to main navigation menu Skip to site footer

The role of stem cell secretome on spinal cord injury regeneration: a systematic review and meta-analysis

  • I Nyoman Semita ,
  • Dwikora Novembri Utomo ,
  • Heri Suroto ,


Abstract

Background: The treatment of spinal cord injuries (SCIs) is a controversial topic and is not yet effective. Stem cell secretome is an emerging alternative treatment that uses the paracrine effect of stem cells. Although there have been many studies on this subject, there are still differences regarding the origin, dose, route of secretome administration, type of experimental animal, phase of the SCI, and outputs evaluated. The topic needs a systematic review and meta-analysis.

Methods: This systematic review and meta-analysis were reported based on criteria from Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The authors searched PubMed, ScienceDirect, Cochrane Library, and Google Scholar with multiple electronic databases until October 2021.

Results: Twenty-eight studies that met the inclusion criteria were included in this research. The stem cell secretome was very beneficial as the axonal regeneration agent (n=12); it increases the locomotor recovery (n=28) and growth factors (n=2) and reduces the size of the cystic cavity (n=1) and lesion extension (n=14). We recognized 28 studies that met our inclusion criteria. Stem cell secretome therapies showed improvement in the locomotor score (standard mean difference [SMD]: 0.94; 95% confidence interval [CI]: 0.75–1.13, p<0.000001, I2=90%) and reduction in the lesion size (SMD: 5.06; 95% CI: 3.44–6.67, p<0.00001, I2=94%).

Conclusion: The stem cell secretome greatly affects treating SCI rodent models. Future studies should focus on chronic SCIs in the primary research, translational research, and neurological research stage of stem cell secretome.

Keywords: Regeneration Stem Cell Secretome Spinal Cord Injury Treatment

References

  1. Tsai MJ, Liou DY, Lin YR, Weng CF, Huang MC, Huang WC, et al. Attenuating Spinal Cord Injury by Conditioned Medium from Bone Marrow Mesenchymal Stem Cells. Clin Med (Northfield Il). 2019;8(23):1-13.
  2. Liu W, Wang Y, Gong F, Rong Y, Luo Y, Tang P, et al. Exosomes Derived from Bone Mesenchymal Stem Cells Repair Traumatic Spinal Cord Injury by Suppressing the Activation of A1 Neurotoxic Reactive Astrocytes. J Neurotrauma. 2019;36(3):469-484.
  3. Asadi-Golshan R, Razban V, Mirzaei E, Rahmanian A, Khajeh S, Mostafavi-Pour Z, et al. Sensory and motor behavior evidences supporting the usefulness of conditioned medium from dental pulp-derived stem cells in spinal cord injury in rats. Asian Spine J. 2018;12(5):785-793.
  4. Chen Y, Tian Z, He L, Liu C, Wang N, ROng L, et al. Exosomes derived from miR-26a-modified MSCs promote axonal regeneration via the PTEN/AKT/mTOR pathway following spinal cord injury. Stem Cell Res Ther. 2021;12(1):1-15.
  5. Borhani-Haghighi M, Navid S, Mohamadi Y. The therapeutic potential of conditioned medium from human breast milk stem cells in treating spinal cord injury. Asian Spine J. 2020;14(2):131-138.
  6. Zhou X, Chu X, Yuan H, Qiu J, Zhao C, Xin D, et al. Mesenchymal stem cell derived EVs mediate neuroprotection after spinal cord injury in rats via the microRNA-21-5p/FasL gene axis. Biomed Pharmacother. 2019;115:108818.
  7. Wang H, Song G, Chuang H, Chiu C, Abdelmaksoud A, Ye Y, et al. Portrait of glial scar in neurological diseases. Int J Immunopathol Pharmacol. 2018;31:1-6.
  8. Willis CM, Nicaise AM, Peruzzotti-Jametti L, Pluchino S. The neural stem cell secretome and its role in brain repair. Brain Res. 2020;1729:146615.
  9. Chudickova M, Vackova I, Urdzikova LM, Jancova P, Kekulova K, Rehorova M, et al. The effect of Wharton jelly-derived mesenchymal stromal cells and their conditioned media in the treatment of a rat spinal cord injury. Int J Mol Sci. 2019;20(18):4516.
  10. Gu M, Gao Z, Li X, Guo L, Lu T, Li Y, et al. Conditioned medium of olfactory ensheathing cells promotes the functional recovery and axonal regeneration after contusive spinal cord injury. Brain Res. 2017;1654(Pt A):43-54.
  11. Cizkova D, Cubinkova V, Smolek T, Murgoci AN, Danko J, Vdoviakova K, et al. Localized intrathecal delivery of mesenchymal stromal cells conditioned medium improves functional recovery in a rat model of spinal cord injury. Int J Mol Sci. 2018;19(3):1-13.
  12. Cheng Z, Bosco DB, Sun L, Chen X, Xu Y, Tai W, et al. Neural stem cell-conditioned medium suppresses inflammation and promotes spinal cord injury recovery. Cell Transplant. 2017;26(3):469-482.
  13. 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.
  14. Pajer K, Bellák T, Nógrádi A. Stem cell secretome for spinal cord repair: Is it more than just a random baseline set of factors? Cells. 2021;10(11):3214.
  15. Liau LL, Looi QH, Chia WC, Subramaniam T, Ng MH, Law JX. Treatment of spinal cord injury with mesenchymal stem cells. Cell Biosci. 2020;10(1):1-17.
  16. Pinho AG, Cibr JR, Silva NA, Monteiro S, Salgado J. Cell Secretome : Basic Insights and Therapeutic Opportunities for CNS Disorders. Pharmaceuticals (Basel). 2020;13(2):31.
  17. Oka S, Yamaki T, Sasaki M, Ukai R, Takemura M, Yokoyama T, et al. Intravenous Infusion of Autoserum-Expanded Autologous Mesenchymal Stem Cells in Patients With Chronic Brain Injury: Protocol for a Phase 2 Trial. JMIR Research Protocols. 2022;11(7):e37898.
  18. Dilogo IH, Fiolin J. Role of Mesenchymal Stem Cell-Conditioned Medium (MSC-CM) in the Bone Regeneration: A Systematic Review from 2007-2018. Annu Res Rev Biol. 2019;31(2):1-16.
  19. Huang JH, Hui C, Yang F, Yin XM, Cao Y, Yue F. Extracellular Vesicles Derived from Epidural Fat ‑ Mesenchymal Stem Cells Attenuate NLRP3 Inflammasome Activation and Improve Functional Recovery After Spinal Cord Injury. Neurochem Res. 2020;45(4):760-771.
  20. Rong Y, Liu W, Wang J, Fan J, Luo Y, Li L, et al. Neural stem cell-derived small extracellular vesicles attenuate apoptosis and neuroinflammation after traumatic spinal cord injury by activating autophagy. Cell Death Dis. 2019;10(5):340.
  21. Zhong D, Cao Y, Li CJ, Li M, Rong ZJ, Jiang L, et al. Highlight article: Neural stem cell-derived exosomes facilitate spinal cord functional recovery after injury by promoting angiogenesis. Exp Biol Med. 2020;245(1):54-65.
  22. Huang JH, Yin XM, Xu Y, Xu CC, Lin X, Ye FB, et al. Systemic Administration of Exosomes Released from Mesenchymal Stromal Cells Attenuates Apoptosis, Inflammation, and Promotes Angiogenesis after Spinal Cord Injury in Rats. J Neurotrauma. 2017;34(24):3388-3396.
  23. Li D, Zhang P, Yao X, Li H, Shen H, Li X, et al. Exosomes derived from miR-133b-modified mesenchymal stem cells promote recovery after spinal cord injury. Front Neurosci. 2018;12(11):1-9.
  24. Huang JH, Xu Y, Yin XM, Lin FY. Exosomes Derived from miR-126-modified MSCs Promote Angiogenesis and Neurogenesis and Attenuate Apoptosis after Spinal Cord Injury in Rats. Neuroscience. 2019;424(11):133-145.
  25. Sun G, Li G, Li D, Huang W, Zhang R, Zhang H, et al. hucMSC derived exosomes promote functional recovery in spinal cord injury mice via attenuating inflammation. Mater Sci Eng C. 2018;89(2017):194-204.
  26. Borges PA, Cristante AF, de Barros-Filho TEP, Natalino RJM, dos Santos GB, Marcon RM. Standardization of a spinal cord lesion model and neurologic evaluation using mice. Clinics. 2018;73:1-6.
  27. Gollie JM, Guccione AA. Overground Locomotor Training in Spinal Cord Injury: A Performance-Based Framework. Top Spinal Cord Inj Rehabil. 2017;23(3):226-233.
  28. Lu Y, Yan Z, Ruiyi Z, Wen L, Wu K, Li Y, et al. Bone Mesenchymal Stem Cell-Derived Extracellular Vesicles Promote Recovery Following Spinal Cord Injury via Improvement of the Integrity of the Blood-Spinal Cord. Front Neurosci. 2019;13(3):209.
  29. Ramalho BDS, De Almeida FM, Sales CM, De Lima S, Martinez AMB. Injection of bone marrow mesenchymal stem cells by intravenous or intraperitoneal routes is a viable alternative to spinal cord injury treatment in mice. Neural Regen Res. 2018;13(6):1046-1053.
  30. Stewart AN, Kendziorski G, Deak ZM, Brown DJ, Fini MN, Copely KL, et al. Co-transplantation of mesenchymal and neural stem cells and overexpressing stromal-derived factor-1 for treating spinal cord injury. Brain Res. 2017;1672:91-105.
  31. Du XJ, Chen YX, Zheng ZC, Wang N, Wang XY, Kong FE. Neural stem cell transplantation inhibits glial cell proliferation and P2X receptor-mediated neuropathic pain in spinal cord injury rats. Neural Regen Res. 2019;14(5):876.
  32. Munter JP d, Beugels J, Munter S, Jansen L, Cillero-Pastor B, Movskin O, et al. Standardized human bone marrow-derived stem cells infusion improves survival and recovery in a rat model of spinal cord injury. J Neurol Sci. 2019;402(5):16-29.
  33. Chen C, Bai GC, Jin HL, Lei K, Li KX. Local injection of bone morphogenetic protein 7 promotes neuronal regeneration and motor function recovery after acute spinal cord injury. Neural Regen Res. 2018;13(6):1054.
  34. Galhom RA, Hussein HH, El A, Ali MHM. Biomedicine & Pharmacotherapy Role of bone marrow derived mesenchymal stromal cells and Schwann-like cells transplantation on spinal cord injury in adult male albino rats. Biomed Pharmacother. 2018;108(5):1365-1375.
  35. Vawda R, Badner A, Hong J, Mikhail M, Dragas R, Xhima K, et al. Harnessing the Secretome of Mesenchymal Stromal Cells for Traumatic Spinal Cord Injury: Multicell Comparison and Assessment of in Vivo Efficacy. Stem Cells Dev. 2020;29(22):1429-1443.
  36. Kanekiyo K, Nakano N, Homma T, Yamada Y, Tamachi M, Suzuki Y, et al. Effects of Multiple Injection of Bone Marrow Mononuclear Cells on Spinal Cord Injury of Rats. J Neurotrauma. 2017;34(21):3003-3011.
  37. Cantinieaux D, Quertainmont R, Blacher S, Rossi L, Wanet T, Noel A, et al. Conditioned Medium from Bone Marrow-Derived Mesenchymal Stem Cells Improves Recovery after Spinal Cord Injury in Rats : An Original Strategy to Avoid Cell Transplantation. 2013;8(8):e69515.
  38. Feng L, Gan H, Zhao W, Liu Y. Effect of transplantation of olfactory ensheathing cell conditioned medium induced bone marrow stromal cells on rats with spinal cord injury. Mol Med Rep. 2017;16(2):1661-1668.
  39. Gilbert EAB, Lakshman N, Lau KSK, Morshead CM. Regulating Endogenous Neural Stem Cell Activation to Promote Spinal Cord Injury Repair. Cells. 2022;11(5):1-26.
  40. Wang S, He Y, Zhang H, Chen L, Cao L, Yang L, et al. The Neural Stem Cell Properties of PKD2L1+ Cerebrospinal Fluid-Contacting Neurons in vitro. Front Cell Neurosci. 2021;15(3):1-11.
  41. Wang L, Pei S, Han L, Guo B, Li Y, Duan R, et al. Mesenchymal Stem Cell-Derived Exosomes Reduce A1 Astrocytes via Downregulation of Phosphorylated NFκB P65 Subunit in Spinal Cord Injury. Cell Physiol Biochem. 2018;50(4):1535-1559.
  42. Zhao C, Zhou X, Qiu J, Xin D, Li T, Chu X, et al. Exosomes derived from bone marrow mesenchymal stem cells inhibit complement activation in rats with spinal cord injury. Drug Des Devel Ther. 2019;13:3693-3704.
  43. Kim HY, Kumar H, Jo MJ, Kim J, Yoon JK, Lee JR, et al. Therapeutic Efficacy-Potentiated and Diseased Organ-Targeting Nanovesicles Derived from Mesenchymal Stem Cells for Spinal Cord Injury Treatment. Nano Lett. 2018;18(8):4965-4975.
  44. Ruppert KA, Nguyen TT, Prabhakara KS, Toledano Furman NE, Srivastava AK, HArting MT, et al. Human Mesenchymal Stromal Cell-Derived Extracellular Vesicles Modify Microglial Response and Improve Clinical Outcomes in Experimental Spinal Cord Injury OPEN. Sci Rep. 2018;8(1):1-12.
  45. Chen YT, Tsai MJ, Hsieh N, Lo MJ, Lee MJ, Cheng H, et al. The superiority of conditioned medium derived from rapidly expanded mesenchymal stem cells for neural repair. Stem Cell Res Ther. 2019;10(1):1-15.
  46. Guo L, Rolfe AJ, Wang X, Tai W, Cheng Z, Cao K, et al. Rescuing macrophage normal function in spinal cord injury with embryonic stem cell conditioned media. Molecular brain. 2016;9(1):1-14.
  47. Shen H, Xu B, Yang C, Xue W, You Z, Wu X, et al. A DAMP-scavenging, IL-10-releasing hydrogel promotes neural regeneration and motor function recovery after spinal cord injury. Biomaterials. 2022;280:121279.
  48. Hellenbrand DJ, Reichl KA, Travis BJ, Fillipp ME, Khalil AS, Pulito DJ, et al. Sustained interleukin-10 delivery reduces inflammation and improves motor function after spinal cord injury. J Neuroinflammation. 2019;16(1):1-19.
  49. 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 Mol Sci. 2017;18(9):1852.
  50. Vismara I, Papa S, Rossi F, Forloni G, Veglianese P. Current Options for Cell Therapy in Spinal Cord Injury. Trends Mol Med. 2017;23(9):831-849.
  51. Liang X, Ding Y, Zhang Y, Tse HF, Lian Q. Paracrine mechanisms of mesenchymal stem cell-based therapy: Current status and perspectives. Cell Transplant. 2014;23(9):1045-1059.
  52. Suyasa IK, Lestari AAW, Prabawa IPY, Marta KKA. Water sport-related spine injury in Bali: a review and preliminary study. Indonesia Journal of Biomedical Science. 2019;13(2):72-76.
  53. Semita IN, Juliasih NN, Purwandhono A, Setyawardani A, Nugraha MY. Spinal cord injury in tuberculous spinal epidural abscess patient with deficiency of vitamin D: a case report with literature review. Bali Medical Journal. 2022;11(3): 1478-1482.

How to Cite

Semita, I. N., Utomo, D. N., & Suroto, H. (2023). The role of stem cell secretome on spinal cord injury regeneration: a systematic review and meta-analysis. Bali Medical Journal, 12(2), 1507–1513. https://doi.org/10.15562/bmj.v12i2.4131
ACM ACS APA ABNT Chicago Harvard IEEE MLA Turabian Vancouver
Download Citation
Endnote/Zotero/Mendeley (RIS) BibTeX

HTML
0

Total
0

Share

Search Panel

I Nyoman Semita
Google Scholar
Pubmed
BMJ Journal

Dwikora Novembri Utomo
Google Scholar
Pubmed
BMJ Journal

Heri Suroto
Google Scholar
Pubmed
BMJ Journal