Intravenous administration exosomes derived from human amniotic mesenchymal stem cells improves neurological recovery after acute traumatic spinal cord injury in rats

Document Type : Original Article

Authors

1 Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China

2 Department of Neurosurgery, Institute of Neuroscience, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China

3 Interventional Department, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China

4 Department of Health Insurance, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China

Abstract

Objective(s): Our previous study has showed that human amniotic mesenchymal stem cells (hAMSCs) transplantation improves neurological recovery after traumatic spinal cord injury (TSCI) in rats. However, less is known about the effects of exosomes derived from hAMSCs for TSCI. Here, we investigated whether hAMSCs-derived exosomes improve neurological recovery in TSCI rats and the underlying mechanisms. 
Materials and Methods: A rat traumatic spinal cord injury (TSCI) mode was established using a weight drop device. At 2 hr after TSCI, rats were administered either hAMSCs-derived exosomes or phosphate buffered saline via the tail vein. Locomotor recovery was evaluated by an open-field locomotor rating scale and gridwalk task. Spinal cord water content, hematoxylin and eosin (H&E) staining, Evans blue (EB) dye extravasation, immunofluorescence staining, and enzyme-linked immunosorbent were performed to elucidate the underlying mechanism.
Results: hAMSCs-derived exosomes significantly reduced the numbers of ED1+ macrophages/microglia and caspase-3+cells and decreased the levels of reactive oxygen species, myeloperoxidase activity and inflammatory cytokines, such as tumor necrosis factor alpha, interleukin-6 and interleukin-1β. In addition, hAMSCs-derived exosomes significantly attenuated spinal cord water content and Evans blue extravasation, and enhanced angiogenesis and axonal regeneration. Finally, hAMSCs-derived exosomes also significantly reduced the lesion volume, inhibited astrogliosis, and improved functional recovery. 
Conclusion: Taken together, these findings demonstrate that hAMSCs-derived exosomes have favourable effects on rats after acute TSCI, and that they may serve as an alternative cell-free therapeutic approach for treating acute TSCI.

Keywords

Main Subjects

References

1. Fouad K, Popovich PG, Kopp MA, Schwab JM. The neuroanatomical-functional paradox in spinal cord injury. Nat Rev Neurol 2021; 17:53-62.
2. Badhiwala JH, Wilson JR, Fehlings MG. Global burden of traumatic brain and spinal cord injury. Lancet Neurol 2019; 18:24-25.
3. Alizadeh A, Dyck SM, Karimi-Abdolrezaee S. Traumatic spinal cord injury: An overview of pathophysiology, models and acute injury mechanisms. Front Neurol 2019; 10:282-306.
4. Assinck P, Duncan GJ, Hilton BJ, Plemel JR, Tetzlaff W. Cell transplantation therapy for spinal cord injury. Nat Neurosci 2017; 20:637-647.
5. Liu QW, Huang QM, Wu HY, Zuo GS, Gu HC, Deng KY, Xin HB. Characteristics and therapeutic potential of human amnion-derived stem cells. Int J Mol Sci 2021; 22:970-100.
6. Nandoe Tewarie RS, Hurtado A, Bartels RH, Grotenhuis A, Oudega M. Stem cell-based therapies for spinal cord injury. J Spinal Cord Med 2009; 32:105-114.
7. Gao L, Peng Y, Xu W, He P, Li T, Lu X, Chen G. Progress in stem cell therapy for spinal cord injury. Stem Cells Int 2020; 2020:2853650.
8. Xia X, Chan KF, Wong GTY, Wang P, Liu L, Yeung BPM, et al. Mesenchymal stem cells promote healing of nonsteroidal anti-inflammatory drug-related peptic ulcer through paracrine actions in pigs. Sci Transl Med 2019; 11:eaat7455.
9. Zhang ZG, Buller B, Chopp M. Exosomes - beyond stem cells for restorative therapy in stroke and neurological injury. Nat Rev Neurol 2019; 15:193-203.
10. Doeppner TR, Herz J, Gorgens A, Schlechter J, Ludwig AK, Radtke S, et al. Extracellular vesicles improve post-stroke neuroregeneration and prevent postischemic immunosuppression. Stem Cells Transl Med 2015; 4:1131-1143.
11. Shao L, Zhang Y, Lan B, Wang J, Zhang Z, Zhang L, et al. MiRNA-sequence indicates that mesenchymal stem cells and exosomes have similar mechanism to enhance cardiac repair. Biomed Res Int 2017; 2017:4150705.
12. Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science 2020; 367: eaau6977.
13. Chen Y, Tian Z, He L, Liu C, Wang N, Rong L, Liu B. 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; 12:224-238.
14. Lai X, Wang Y, Wang X, Liu B, Rong L. miR-146a-5p-modified hUCMSC-derived exosomes facilitate spinal cord function recovery by targeting neurotoxic astrocytes. Stem Cell Res Ther 2022; 13:487-510.
15. Ren Z, Qi Y, Sun S, Tao Y, Shi R. Mesenchymal stem cell-derived exosomes: hope for spinal cord injury repair. Stem Cells Dev 2020; 29:1467-1478.
16. Zhou HL, Zhang XJ, Zhang MY, Yan ZJ, Xu ZM, Xu RX. Transplantation of human amniotic mesenchymal stem cells promotes functional recovery in a rat model of traumatic spinal cord injury. Neurochem Res 2016; 41:2708-2718.
17. Zhou HL, Fang H, Luo HT, Ye MH, Yu GY, Zhang Y, et al. Intravenous administration of human amniotic mesenchymal stem cells improves outcomes in rats with acute traumatic spinal cord injury. Neuroreport 2020; 31:730-736.
18. Kapfhammer JP. Axon sprouting in the spinal cord: growth promoting and growth inhibitory mechanisms. Anat Embryol (Berl) 1997; 196:417-426.
19. Perrin FE, Noristani HN. Serotonergic mechanisms in spinal cord injury. Exp Neurol 2019; 318:174-191.
20. 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; 7:92-110.
21. Rahmani A, Saleki K, Javanmehr N, Khodaparast J, Saadat P, Nouri HR. Mesenchymal stem cell-derived extracellular vesicle-based therapies protect against coupled degeneration of the central nervous and vascular systems in stroke. Ageing Res Rev 2020; 62:101106.
22. Liu X, Zhang Y, Wang Y, Qian T. Inflammatory response to spinal cord injury and its treatment. World Neurosurg 2021; 155:19-31.
23. Hellenbrand DJ, Quinn CM, Piper ZJ, Morehouse CN, Fixel JA, Hanna AS. Inflammation after spinal cord injury: A review of the critical timeline of signaling cues and cellular infiltration. J Neuroinflammation 2021; 18:284-297.
24. Park J, Decker JT, Margul DJ, Smith DR, Cummings BJ, Anderson AJ, Shea LD. Local immunomodulation with anti-inflammatory cytokine-encoding lentivirus enhances functional recovery after spinal cord injury. Mol Ther 2018; 26:1756-1770.
25. Wang C, Wang M, Xia K, Wang J, Cheng F, Shi K, et al. A bioactive injectable self-healing anti-inflammatory hydrogel with ultralong extracellular vesicles release synergistically enhances motor functional recovery of spinal cord injury. Bioact Mater 2021; 6:2523-2534.
26. Jiang Z, Zhang J. Mesenchymal stem cell-derived exosomes containing miR-145-5p reduce inflammation in spinal cord injury by regulating the TLR4/NF-kappaB signaling pathway. Cell Cycle 2021; 20:993-1009.
27. 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 Mater Biol Appl 2018; 89:194-204.
28. Clifford T, Finkel Z, Rodriguez B, Joseph A, Cai L. Current advancements in spinal cord injury research-glial scar formation and neural regeneration. Cells 2023; 12: 853-872.
29. Moulson AJ, Squair JW, Franklin RJM, Tetzlaff W, Assinck P. Diversity of reactive astrogliosis in cns pathology: Heterogeneity or plasticity? Front Cell Neurosci 2021; 15:703810.
30. Vangansewinkel T, Lemmens S, Tiane A, Geurts N, Dooley D, Vanmierlo T, et al. Therapeutic administration of mouse mast cell protease 6 improves functional recovery after traumatic spinal cord injury in mice by promoting remyelination and reducing glial scar formation. FASEB J 2023; 37:e22939.
31. Ohtake Y, Li S. Molecular mechanisms of scar-sourced axon growth inhibitors. Brain Res 2015; 1619:22-35.
32. Deng J, Li M, Meng F, Liu Z, Wang S, Zhang Y, et al. 3D Spheroids of human placenta-derived mesenchymal stem cells attenuate spinal cord injury in mice. Cell Death Dis 2021; 12:1096.
33. Lale Ataei M, Karimipour M, Shahabi P, Pashaei-Asl R, Ebrahimie E, Pashaiasl M. The restorative effect of human amniotic fluid stem cells on spinal cord injury. Cells 2021; 10:2565.-2579
34. Pieczonka K, Nakashima H, Nagoshi N, Yokota K, Hong J, Badner A, et al. Human spinal oligodendrogenic neural progenitor cells enhance pathophysiological outcomes and functional recovery in a clinically relevant cervical spinal cord injury rat model. Stem Cells Transl Med 2023; 12:603-616.
35. Oswald MCW, Garnham N, Sweeney ST, Landgraf M. Regulation of neuronal development and function by ROS. FEBS Lett 2018; 592:679-691.
36. Kumar S, Theis T, Tschang M, Nagaraj V, Berthiaume F. Reactive oxygen species and pressure ulcer formation after traumatic injury to spinal cord and brain. Antioxidants (Basel) 2021; 10:1013-1027.
37. Jia Z, Zhu H, Li J, Wang X, Misra H, Li Y. Oxidative stress in spinal cord injury and anti-oxidant-based intervention. Spinal Cord 2012; 50:264-274.
38. Ji ZS, Gao GB, Ma YM, Luo JX, Zhang GW, Yang H, et al. Highly bioactive iridium metal-complex alleviates spinal cord injury via ROS scavenging and inflammation reduction. Biomaterials 2022; 284:121481.
39. Luo W, Wang Y, Lin F, Liu Y, Gu R, Liu W, Xiao C. Selenium-doped carbon quantum dots efficiently ameliorate secondary spinal cord injury via scavenging reactive oxygen species. Int J Nanomedicine 2020; 15:10113-10125.
40. Ding C, Qian C, Hou S, Lu J, Zou Q, Li H, Huang B. Exosomal miRNA-320a is released from hAMSCs and regulates SIRT4 to prevent reactive oxygen species generation in POI. Mol Ther Nucleic Acids 2020; 21:37-50.
41. Yao C, Cao X, Yu B. Revascularization after traumatic spinal cord injury. Front Physiol 2021;12:631500.
42. Rauch MF, Hynes SR, Bertram J, Redmond A, Robinson R, Williams C, et al. Engineering angiogenesis following spinal cord injury: A coculture of neural progenitor and endothelial cells in a degradable polymer implant leads to an increase in vessel density and formation of the blood-spinal cord barrier. Eur J Neurosci 2009; 29:132-145.
43. Siddiqui AM, Oswald D, Papamichalopoulos S, Kelly D, Summer P, Polzin M, et al. Defining spatial relationships between spinal cord axons and blood vessels in hydrogel scaffolds. Tissue Eng Part A 2021; 27:648-664.
44. Bucan V, Vaslaitis D, Peck CT, Strauss S, Vogt PM, Radtke C. Effect of exosomes from rat adipose-derived mesenchymal stem cells on neurite outgrowth and sciatic nerve regeneration after crush injury. Mol Neurobiol 2019; 56:1812-1824.
45. Zhang C, Zhang C, Xu Y, Li C, Cao Y, Li P. Exosomes derived from human placenta-derived mesenchymal stem cells improve neurologic function by promoting angiogenesis after spinal cord injury. Neurosci Lett 2020; 739:135399.
46. Bartanusz V, Jezova D, Alajajian B, Digicaylioglu M. The blood-spinal cord barrier: morphology and clinical implications. Ann Neurol 2011; 70:194-206.
47. Jin LY, Li J, Wang KF, Xia WW, Zhu ZQ, Wang CR, et al. Blood-spinal cord barrier in spinal cord injury: A review. J Neurotrauma 2021; 38:1203-1224.
48. Kumar H, Ropper AE, Lee SH, Han I. Propitious therapeutic modulators to prevent blood-spinal cord barrier disruption in spinal cord injury. Mol Neurobiol 2017; 54:3578-3590.
 
 
Iranian Journal of Basic Medical Sciences
Volume 27, Issue 10
October 2024
Pages 1284-1292

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