Bone marrow stromal cell-conditioned medium regenerates injured sciatic nerve by increasing expression of MPZ and NGF and decreasing apoptosis

Document Type : Original Article

Authors

1 Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran

2 Department of Anatomy, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran

3 Laboratory of Learning and Memory, Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran

4 Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran

5 Department of Physiology, Molecular and Cell Biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran

6 Medical Biotechnology Research Center, Department of Physiology, School of Paramedicine, Guilan University of Medical Sciences, Rasht, Iran

Abstract

Objective(s): Despite the many benefits of mesenchymal stem cell (MSC) transplantation for tissue regeneration, there are some limitations to using them, including the high costs, applying invasive procedures, the possibility of transplant rejection, and cell malignancy. This study aimed to investigate the effect of secretions of bone marrow stromal cells (BMSCs) with the cell-free strategy on damaged sciatic nerve with an emphasis on the role of apoptosis and the expression of myelin protein zero (MPZ) and nerve growth factor (NGF) proteins.
Materials and Methods: BMSCs were cultured and a 25-fold concentrated conditioned medium (CM) from the cells was provided. After creating a crush injury in the left sciatic nerve of male rats, BMSCs or CM were injected into the injured site of the nerve. Four weeks later, the expression of MPZ, NGF, Bax, and Bcl-2 proteins in the sciatic nerve and histological parameters of the sciatic nerve and gastrocnemius muscle were assessed.
Results: The results demonstrated that injection of CM decreased apoptosis and increased expression of MPZ and NGF proteins, improving remyelination and regeneration of the sciatic nerve almost as much as the transplantation of the BMSCs themselves compared to the control group.
Conclusion: The results suggest that BMSC secretions may improve remyelination and regeneration of damaged sciatic nerve by increasing the expression of MPZ and NGF and decreasing apoptosis.

Keywords

Main Subjects

References

1. Li R, Liu Z, Pan Y, Chen L, Zhang Z, Lu L. Peripheral nerve injuries treatment: a systematic review. Cell Biochem Biophys 2014; 68:449-454.
2. Gaudin R, Knipfer C, Henningsen A, Smeets R, Heiland M, Hadlock T. Approaches to peripheral nerve repair: generations of biomaterial conduits yielding to replacing autologous nerve grafts in craniomaxillofacial surgery. Biomed Res Int 2016; 2016:3856262.
3. Gordon T. Electrical stimulation to enhance axon regeneration after peripheral nerve injuries in animal models and humans. Neurotherapeutics 2016; 13:295-310.
4. da Silva JT, Santos FM, Giardini AC, Martins Dde O, de Oliveira ME, Ciena AP, et al. Neural mobilization promotes nerve regeneration by nerve growth factor and myelin protein zero increased after sciatic nerve injury. Growth Factors 2015; 33:8-13.
5. Feng S, Zhuang M, Wu R. Secretion of nerve growth factor, brain-derived neurotrophic factor, and glial cell-line derived neurotrophic factor in co-culture of four cell types in cerebrospinal fluid-containing medium. Neural Regen Res 2012; 7:2907-2914.
6. Zarbakhsh S, Goudarzi N, Shirmohammadi M, Safari M. Histological study of bone marrow and umbilical cord stromal cell transplantation in regenerating rat peripheral nerve. Cell J 2016; 17:668-677.
7. Gu JH, Ji YH, Dhong ES, Kim DH, Yoon ES. Transplantation of adipose derived stem cells for peripheral nerve regeneration in sciatic nerve defects of the rat. Curr Stem Cell Res Ther 2012; 7:347-355.
8. Fu X, Liu G, Halim A, Ju Y, Luo Q, Song AG. Mesenchymal stem cell migration and tissue repair. Cells 2019; 8: 784-801.
9. Baglio SR, Pegtel DM, Baldini N. Mesenchymal stem cell secreted vesicles provide novel opportunities in (stem) cell-free therapy. Front Physiol 2012; 3:359-369.
10. Yang D, Wang W, Li L, Peng Y, Chen P, Huang H, et al. The relative contribution of paracine effect versus direct differentiation on adipose-derived stem cell transplantation mediated cardiac repair. PLoS One 2013; 8:e59020.
11. Gnecchi M, Danieli P, Malpasso G, Ciuffreda MC. Paracrine mechanisms of mesenchymal stem cells in tissue repair. Methods Mol Biol 2016; 1416:123-146.
12. Lin H, Chen H, Zhao X, Chen Z, Zhang P, Tian Y, et al. Advances in mesenchymal stem cell conditioned medium-mediated periodontal tissue regeneration. J Transl Med 2021; 19:456-468.
13. Khanmohammadi N, Sameni HR, Mohammadi M, Pakdel A, Mirmohammadkhani M, Parsaie H, et al. Effect of transplantation of bone marrow stromal cell- conditioned medium on ovarian function, morphology and cell death in cyclophosphamide-treated rats. Cell J 2018; 20:10-18.
14. Haydari S, Safari M, Zarbakhsh S, Bandegi AR, Miladi-Gorji H. Effects of voluntary exercise on the viability, proliferation and BDNF levels of bone marrow stromal cells in rat pups born from morphine- dependent mothers during pregnancy. Neurosci Lett 2016; 634:132-137.
15. Safari M, Jafari B, Zarbakhsh S, Sameni H, Vafaei AA, Mohammadi NK, et al. G-CSF for mobilizing transplanted bone marrow stem cells in rat model of Parkinson’s disease. Iran J Basic Med Sci 2016; 19:1318-1324.
16. Sameni HR, Seiri M, Safari M, Tabrizi Amjad MH, Khanmohammadi N, Zarbakhsh S. Bone marrow stromal cells with the granulocyte colony-stimulating factor in the management of chemotherapy-induced ovarian failure in a rat model. Iran J Med Sci 2019; 44:135-145.
17. Abdolmaleki A, Zahri S, Bayrami A. Rosuvastatin enhanced functional recovery after sciatic nerve injury in the rat. Eur J Pharmacol 2020; 882:173260.
18. Rodriguez Sanchez DN, de Lima Resende LA, Boff Araujo Pinto G, de Carvalho Bovolato AL, Possebon FS, Deffune E, et al. Canine adipose-derived mesenchymal stromal cells enhance neuroregeneration in a rat model of sciatic nerve crush injury. Cell Transplant 2019; 28:47-54.
19. Hei WH, Almansoori AA, Sung MA, Ju KW, Seo N, Lee SH, et al. Adenovirus vector-mediated ex vivo gene transfer of brain-derived neurotrophic factor (BDNF) tohuman umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) promotescrush-injured rat sciatic nerve regeneration. Neurosci Lett 2017; 643:111-120.
20. Semis HS, Kandemir FM, Caglayan C, Kaynar O, Genc A, Arikan SM. Protective effect of naringin against oxaliplatin-induced peripheral neuropathy in rats: A behavioral and molecular study. J Biochem Mol Toxicol 2022; 36:e23121.
21. Hao GM, Liu YG, Wu Y, Xing W, Guo SZ, Wang Y, et al. The protective effect of the active components of ERPC on diabetic peripheral neuropathy in rats. J Ethnopharmacol 2017; 202:162-171.
22. La G, Zhou M, Lim JY, Oh S, Xing H, Liu N, et al. Proteomics and transcriptomics analysis reveals clues into the mechanism of the beneficial effect of electrical stimulation on rat denervated gastrocnemius muscle. Cell Physiol Biochem 2019; 52:769-786.
23. Zarbakhsh S, Moradi F, Joghataei MT, Bahktiari M, Mansouri K, Abedinzadeh M. Evaluation of the functional recovery in sciatic nerve injury following the co-transplantation of schwann and bone marrow stromal stem cells in rat. Basic Clin Neurosci 2013; 4:291-298.
24. Bogatcheva NV, Coleman ME. Conditioned medium of mesenchymal stromal cells: A new class of therapeutics. Biochemistry (Mosc) 2019; 84:1375-1389.
25. Pawitan JA. Prospect of stem cell conditioned medium in regenerative medicine. Biomed Res Int 2014; 2014:965849.
26. Lee SK, Lee SC, Kim SJ. A novel cell-free strategy for promoting mouse liver regeneration: Utilization of a conditioned medium from adipose-derived stem cells. Hepatol Int 2015; 9:310-320.
27. Shy ME. Peripheral neuropathies caused by mutations in the myelin protein zero. J Neurol Sci 2006; 242:55-66.
28. Ghanbari A, Ghasemi S, Zarbakhsh S. Exercise induced myelin protein zero improvement in neuropathic pain rats. Somatosens Mot Res 2023:1-6.
29. Li R, Li D, Wu C, Ye L, Wu Y, Yuan Y, et al. Nerve growth factor activates autophagy in Schwann cells to enhance myelin debris clearance and to expedite nerve regeneration. Theranostics 2020; 10:1649-1677.
30. Chen CJ, Ou YC, Liao SL, Chen WY, Chen SY, Wu CW, et al. Transplantation of bone marrow stromal cells for peripheral nerve repair. Exp Neurol 2007; 204:443-453.
31. Ramli K, Aminath Gasim I, Ahmad AA, Hassan S, Law ZK, Tan GC, et al. Human bone marrow-derived MSCs spontaneously express specific Schwann cell markers. Cell Biol Int 2019; 43:233-252.
32. Mathot F, Rbia N, Thaler R, Dietz AB, van Wijnen AJ, Bishop AT, et al. Gene expression profiles of human adipose-derived mesenchymal stem cells dynamically seeded on clinically available processed nerve allografts and collagen nerve guides. Neural Regen Res 2021; 16:1613-1621.
33. Yang J, Wu H, Hu N, Gu X, Ding F. Effects of bone marrow stromal cell-conditioned medium on primary cultures of peripheral nerve tissues and cells. Neurochem Res 2009; 34:1685-1694.
34. Bai Q, Zou M, Zhang J, Tian Y, Wu F, Gao B, et al. NGF mediates protection of mesenchymal stem cells-conditioned medium against 2,5-hexanedione-induced apoptosis of VSC4.1 cells via Akt/Bad pathway. Mol Cell Biochem 2020; 469:53-64.
35. Al-Massri KF, Ahmed LA, El-Abhar HS. Mesenchymal stem cells in chemotherapy-induced peripheral neuropathy: A new challenging approach that requires further investigations. J Tissue Eng Regen Med 2020; 14:108-122.
36. Wang Q, Sun G, Gao C, Feng L, Zhang Y, Hao J, et al. Bone marrow mesenchymal stem cells attenuate 2,5-hexanedione-induced neuronal apoptosis through a NGF/AKT-dependent pathway. Sci Rep 2016; 6:34715.
37. Yang JP, Liu HJ, Yang H, Feng PY. Therapeutic time window for the neuroprotective effects of NGF when administered after focal cerebral ischemia. Neurol Sci 2011; 32:433-441.
38. Ma Y, Ge S, Zhang J, Zhou D, Li L, Wang X, et al. Mesenchymal stem cell-derived extracellular vesicles promote nerve regeneration after sciatic nerve crush injury in rats. Int J Clin Exp Pathol 2017; 10:10032-10039.
39. Sugimura-Wakayama Y, Katagiri W, Osugi M, Kawai T, Ogata K, Sakaguchi K, et al. Peripheral nerve regeneration by secretomes of stem cells from human exfoliated deciduous teeth. Stem Cells Dev 2015; 24:2687-2699.
40. Sivanarayanan TB, Bhat IA, Sharun K, Palakkara S, Singh R, Remya t, et al. Allogenic bone marrow-derived mesenchymal stem cells and its conditioned media for repairing acute and sub-acute peripheral nerve injuries in a rabbit model. Tissue Cell 2023; 82:102053.
41. Namini MS, Ebrahimi-Barough S, Ai J, Jahromi HK, Mikaeiliagah E, Azami M, et al. Tissue-engineered core-shell silk-fibroin/poly-l-lactic acid nerve guidance conduit containing encapsulated exosomes of human endometrial stem cells promotes peripheral nerve regeneration. ACS Biomater Sci Eng 2023; 9:3496-3511.
42. Brune JC, Tormin A, Johansson MC, Rissler P, Brosjo O, Lofvenberg R, et al. Mesenchymal stromal cells from primary osteosarcoma are non-malignant and strikingly similar to their bone marrow counterparts. Int J Cancer 2011; 129:319-330.
43. Yu J, Ye K, Li J, Wei Y, Zhou J, Ni W, et al. Schwann-like cell conditioned medium promotes angiogenesis and nerve regeneration. Cell Tissue Bank 2022; 23:101-118.
Iranian Journal of Basic Medical Sciences
Volume 27, Issue 5
May 2024
Pages 596-602

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