Periferik nöropatide subakut dönemde uygulanan mezenkimal kök hücrelerin etkileri
Year 2024,
Volume: 49 Issue: 2, 424 - 438, 30.06.2024
Olcay Kıroğlu
,
Erkan Maytalman
,
Ares Alizade
,
Mustafa Emre
,
Suzan Zorludemir
,
Fazilet Aksu
Abstract
Amaç: Farelerde periferik sinir hasarı oluşturulduktan sonra subakut dönemde uygulanan kemik iliği kökenli mezenkimal kök hücrelerin (Kİ-MKH) 24 haftada nöropatik ağrı ve sinir-kas dokusu fonksiyonları üzerindeki etkilerinin araştırılması amaçlanmıştır.
Gereç ve Yöntem: Farelerde periferik nöropati, siyatik sinir parsiyel ligasyonu yapılarak oluşturuldu. Deneyler Kontrol, Sham, Nöropatik, Kİ-MKH, Nöropatik+Kİ-MKH gruplarında gerçekleştirildi. Allodini, 2.,6. ve 24. haftalarda soğuk plak latens testi ile ölçüldü. 24. haftanın sonunda tüm gruplardan izole edilen sinir-kas dokularında elektrofizyolojik ve histopatolojik incelemeler yapıldı.
Bulgular: Allodini eşiğinin Nöropati+Kİ-MKH grubunda (7.76 ±0.33 sn) nöropati grubuna (4.36±0.21 sn) göre 6. haftadan itibaren arttığı ve 24 hafta boyunca devam ettiği gösterildi. 24. haftada izole edilen sinir dokusunun elektrofizyolojik ölçümleri sonucu, Nöropati+Kİ-MKH grubunun aksiyon potansiyeli (137.9±7.85 mV) ve depolarizasyon (0.74 ± 0.01 ms) değerlerinin nöropati grubuna göre (sırasıyla; 121.5 ±3.03 mV ve 0.81 ± 0.02 ms) kısmi iyileşme gösterdiği belirlendi. Aynı şekilde kas dokusunun istirahat membran potansiyel değerlerinin Nöropati+ Kİ-MKH grubunda nöropati grubuna göre (sırasıyla; -73.4±0.2 ve -87.7±0.2 mV) artmış olduğu ölçüldü. Sinir dokusunun histopatolojik incelemesi sonu nöropati grubunda sinir liflerinin miyelinli aksonlarında kayıp ve endonöryumda belirgin fibrozis, Nöropati+Kİ-MKH grubunda ise Schwann hücre proliferasyonu, sinir liflerinin miyelinli aksonlarının korunduğu görüldü. Kas dokusunun histopatolojik incelemesinde Nöropati grubunda kas lifi atrofisi, kompansatuar hipertrofi lifleri ve artmış iç çekirdekler görülürken, Nöropati+ Kİ-MKH grubunda küçük atrofik kas lifi grupları belirlendi.
Sonuç: Periferik nöropatide, subakut dönemde Kİ-MKH uygulamasının, nöropati grubuna göre hem nöropatik allodiniyi azaltma hem de sinir-kas dokusunda daha fazla fonksiyonel iyileşme sağladığı tespit edildi.
Ethical Statement
Ethical approval was obtained from the Local Ethics Committee of Animal Experiments of Cukurova University with the decision dated 29.11.2011 and numbered 17.
Supporting Institution
This study was supported by grants from theCukurova University Scientific Research Projects Unit, project no. TF2011BAP12.
Thanks
We would like to thank Berk Çelikyürek for his editing contributions.
References
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- Seltzer Z, Dubner R, Shir Y. A novel behavioral model of neuropathic pain disorders produce in rats by partial sciatic nerve injury. Pain.1990;43:205-18.
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- Allchorne AJ, Broom DC, Woolf CJ. Detection of cold pain, cold allodynia and cold hyperalgesia in freely behaving rats, Mol Pain. 2005;1:36.
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- Santiago LY, Clavijo-Alvarez J, Brayfield C, Rubin JP, Marra KG. Delivery of adipose-derived precursor cells for peripheral nerve repair. Cell Transplant. 2009;18:145–58.
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- Huang H, Young W, Chen L, Feng S, Zoubi ZMA, Sharma HS et al. Clinical cell therapy guidelines for neurorestoration (IANR/CANR 2017). Cell Transplant. 2018;27:310-24.
- Kim JW, Ha KY, Molon JN, Kim YH. Bone marrow-derived mesenchymal stem cell transplantation for chronic spinal cord injury in rats: comparative study between intralesional and intravenous transplantation. Spine. 2013;38:1065-74.
- Siniscalco D, Giordano C, Galderisi U, Luongo L, Alessio N, Di Bernardo G et al. Intra-brain microinjection of human mesenchymal stem cells decreases allodynia in neuropathic mice. Cell Mol Life Sci. 2010;67:655–69.
- Oliveira JT, Almeida FM, Biancalana A, Baptista AF, Tomaz MA, Melo PA et al. Mesenchymal stem cells in a polycaprolactone conduit enhance median-nerve regeneration, prevent decrease of creatine phosphokinase levels in muscle, and improve functional recovery in mice. Neuroscience. 2010;170: 1295–303.
- Tondreau T, Lagneaux L, Dejeneffe M, Massy M, Mortier C, Delforge A et al. Bone marrow-derived mesenchymal stem cells already express specific neural proteins before any differentiation. Differentiation. 2004;72:319-26.
- Kinnaird T, Stabile E, Burnett MS, Shou M, Lee CW, Barr S et al. Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrinemechanisms, Circulation. 2004;109:1543–49.
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- Raisi A1, Azizi S, Delirezh N, Heshmatian B, Farshid AA, Amini K. The mesenchymal stem cell-derived microvesicles enhance sciatic nerve regeneration in rat: a novel approach in peripheral nerve cell therapy. J Trauma Acute Care Surg. 2014;76:991-7.
The effects of mesenchymal stem cells applied during the subacute period in peripheral neuropathy
Year 2024,
Volume: 49 Issue: 2, 424 - 438, 30.06.2024
Olcay Kıroğlu
,
Erkan Maytalman
,
Ares Alizade
,
Mustafa Emre
,
Suzan Zorludemir
,
Fazilet Aksu
Abstract
Purpose: The study aims to investigate the effect of bone marrow-derived mesenchymal stem cells (BM-MSCs) administered subacute period to neuropathic mice on allodynia and nerve-muscle tissue functions during 24 weeks.
Materials and Methods: Peripheral neuropathy was induced by partial sciatic nerve ligation. Experiments were conducted in Control, Sham, Neuropathic, BM-MSC, and Neuropathic+BM-MSC groups. Allodynia was measured by cold plate test at the 2nd, 6th, and 24th weeks. Electrophysiological and histopathological examinations were performed on isolated nerve-muscle tissues at the end of the 24th week.
Results: Allodynia threshold increased in the Neuropathic+BM-MSC group (7.76±0.33 sec) from the 6th week and continued to increase along 24 weeks compared to the Neuropathic group (4.36±0.21 sec). Action potential (137.9±7.85 mV) and depolarization (0.74±0.01 msec) values of the Neuropathic+BM-MSC group exhibited partial improvement compared to the Neuropathic group (121.5±3.03 mV and 0.81±0.02 msec, respectively) at the 24th week. Muscle tissue's resting membrane potential values increased in the Neuropathic+BM-MSC group compared to the Neuropathic group (-73.4±0.2 and -87.7±0.2 mV, respectively). Histopathological examination of nerve tissue revealed loss of myelinated axons and significant fibrosis in the endoneurium in the Neuropathic group while Schwann cell proliferation and preservation of myelinated axons were observed in the Neuropathic+BM-MSC group. Muscle fiber atrophy, compensatory hypertrophic fibers, and increased central nuclei were seen in the Neuropathic group, while small atrophic muscle fiber groups were identified in the Neuropathic+BM-MSC group.
Conclusion: BM-MSC application in the subacute period is found to reduce allodynia and provide functional recovery in nerve-muscle tissue in experimental peripheral neuropathy.
References
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- Gaudet AD, Popovich PG, Ramer MS. Wallerian degeneration: gaining perspective on inflammatory events after peripheral nerve injury. J Neuroinflammation. 2011; 8:110.
- Ciaramitaro P, Mondelli M, Logullo F, Grimaldi S, Battiston B, Sard A et al. Italian network for traumatic neuropathies. Traumatic peripheral nerve injuries: epidemiological findings, neuropathic pain and quality of life in 158 patients. J Peripher Nerv Syst. 2010;15:120-7.
- Dieleman JP, Kerklaan J, Huygen FJ, Bouma PA, Sturkenboom MC. Incidence rates and treatment of neuropathic pain conditions in the general population. Pain. 2008;137:681-8.
- Finnerup NB, Otto M, McQuay HJ. Algorithm for neuropathic pain treatment: an evidence based proposal. Pain. 2005;118:289–305.
- Joyce N, Annett G, Wirthlin L, Olson S, Bauer G, Nolta JA. Mesenchymal stem cells for the treatment of neurodegenerative disease. Regen Med. 2010;5:933-46.
- Jin HJ, Bae YK, Kim M, Kwon SJ, Jeon HB, Choi SJ et al. Comparative analysis of human mesenchymal stem cells from bone marrow, adipose tissue, and umbilical cord blood as sources of cell therapy. Int J Mol Sci. 2013;14:17986-8001.
- Blondheim NR, Levy YS, Ben-Zur T, Burshtein A, Cherlow T, Kan I et al. Human mesenchymal stem cells express eural genes, suggesting a neural predisposition. Stem Cells Dev. 2006;15:141-64.
- Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284:143-7.
- Stern-Straeter J, Bonaterra GA, Juritz S, Birk R, Goessler UR, Bieback K et al. Evaluation of the effects of different culture media on the myogenic differentiation potential of adipose tissue- or bone marrow-derived human mesenchymal stem cells. Int J Mol Med. 2014;33:160-70.
- Hosseini M, Yousefifard M, Aziznejad H, Nasirinezhad F. The effect of bone marrow-derived mesenchymal stem cell transplantation on allodynia and hyperalgesia in neuropathic animals: a systematic review with meta-analysis. Biol Blood Marrow Transplant. 2015;21:1537-44.
- Seltzer Z, Dubner R, Shir Y. A novel behavioral model of neuropathic pain disorders produce in rats by partial sciatic nerve injury. Pain.1990;43:205-18.
- Muñoz-Elías G, Woodbury D, Black IB. Marrow stromal cells, mitosis, and neuronal differentiation: stem cell and precursor functions. Stem Cells. 2003;21:437-48.
- Allchorne AJ, Broom DC, Woolf CJ. Detection of cold pain, cold allodynia and cold hyperalgesia in freely behaving rats, Mol Pain. 2005;1:36.
- Han JW, Choi D, Lee MY, Huh YH, Yoon YS. Bone marrow-derived mesenchymal stem cells improve diabetic neuropathy by direct modulation of both angiogenesis and myelination in peripheral nerves. Cell Transplant. 2016;25:313-26.
- Vaquero J, Zurita M, Oya S, Santos M. Cell therapy using bone marrow stromal cells in chronic paraplegic rats: systemic or local administration?. Neurosci Lett. 2006;398:129-34.
- Santiago LY, Clavijo-Alvarez J, Brayfield C, Rubin JP, Marra KG. Delivery of adipose-derived precursor cells for peripheral nerve repair. Cell Transplant. 2009;18:145–58.
- Keilhoff G, Fansa H. Mesenchymal stem cells for peripheral nerve regeneration--a real hope or just an empty promise? Exp Neurol. 2011;232:110-3.
- Lee KH, Suh-Kim H, Choi JS, Jeun S, Kim EJ, Kim S et al. Human mesenchymal stem cell transplantation promotes functional recovery following acute spinal cord injury in rats. Acta Neurobiol Exp.2007;67:13–22.
- Musolino PL, Coronel MF, Hokfelt T, Villar MJ. Bone marrow stromal cells induce changes in pain behavior after sciatic nerve constriction. Neurosci Lett. 2007;418:97–101.
- Guo W, Wang H, Zou S, Gu M, Watanabe M, Wei F et al. Bone marrow stromal cells produce long‐term pain relief in rat models of persistent pain. Stem Cells. 2011;29:1294–303.
- Roh DH, Seo MS, Choi HS, Park SB, Han HJ, Beitz AJ et al. Transplantation of human umbilical cord blood or amniotic epithelial stem cells alleviates mechanical allodynia after spinal cord injury in rats. Cell Transplant. 2013;22:1577–90.
- Schäfer S, Berger JV, Deumens R, Goursaud S, Hanisch UK, Hermans E. Influence of intrathecal delivery of bone marrow-derived mesenchymal stem cells on spinal inflammation and pain hypersensitivity in a rat model of peripheral nerve injury. J Neuroinflammation. 2014;11:157.
- 24. Amemori T, Jendelová P, Ruzicková K, Arboleda D, Syková E. Cotransplantation of olfactory ensheathing glia and mesenchymal stromal cells does not have synergistic effects after spinal cord injury in the rat. Cytotherapy. 2010;12:212–25.
- Huang P, Gebhart N, Richelson E, Brott TG, Meschia JF, Zubair AC. Mechanism of mesenchymal stem cell-induced neuron recovery and anti-inflammation. Cytotherapy. 2014 ;16:1336-44.
- Siniscalco D, Giordano C, Galderisi U, Luongo L, de Novellis V, Rossi F et al. Long-lasting effects of human mesenchymal stem cell systemic administration on pain-like behaviors, cellular, and biomolecular modifications in neuropathic ice. Front Integr Neurosci. 2011;5:79.
- Matthes SM, Reimers K, Janssen I, Liebsch C, Kocsis JD, Vogt PM et al. Intravenous transplantation of mesenchymal stromal cells to enhance peripheral nerve regeneration. Biomed Res Int. 2013;2013:573169.
- Dimarino AM, Caplan AI, Bonfield TL. Mesenchymal stem cells in tissue repair. Front Immunol. 2013;4:201.
- Mukhamedshina YO, Gracheva OA, Mukhutdinova DM, Chelyshev YA, Rizvanov AA. Mesenchymal stem cells and the neuronal microenvironment in the area of spinal cord injury. Neural Regen Res. 2019;14:227-37.
- Huang H, Young W, Chen L, Feng S, Zoubi ZMA, Sharma HS et al. Clinical cell therapy guidelines for neurorestoration (IANR/CANR 2017). Cell Transplant. 2018;27:310-24.
- Kim JW, Ha KY, Molon JN, Kim YH. Bone marrow-derived mesenchymal stem cell transplantation for chronic spinal cord injury in rats: comparative study between intralesional and intravenous transplantation. Spine. 2013;38:1065-74.
- Siniscalco D, Giordano C, Galderisi U, Luongo L, Alessio N, Di Bernardo G et al. Intra-brain microinjection of human mesenchymal stem cells decreases allodynia in neuropathic mice. Cell Mol Life Sci. 2010;67:655–69.
- Oliveira JT, Almeida FM, Biancalana A, Baptista AF, Tomaz MA, Melo PA et al. Mesenchymal stem cells in a polycaprolactone conduit enhance median-nerve regeneration, prevent decrease of creatine phosphokinase levels in muscle, and improve functional recovery in mice. Neuroscience. 2010;170: 1295–303.
- Tondreau T, Lagneaux L, Dejeneffe M, Massy M, Mortier C, Delforge A et al. Bone marrow-derived mesenchymal stem cells already express specific neural proteins before any differentiation. Differentiation. 2004;72:319-26.
- Kinnaird T, Stabile E, Burnett MS, Shou M, Lee CW, Barr S et al. Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrinemechanisms, Circulation. 2004;109:1543–49.
- Benowitz LI, Popovich PG. Inflammation and axon regeneration.Curr Opin Neurol. 2011;24:577-83.
- Dib-Hajj SD, Fjell J, Cummins TR, Zheng Z, Fried K, LaMotte R et al. Plasticity of sodium channel expression in DRG neurons in the chronic constriction injury model of neuropathic pain. Pain. 1999; 83:591–600.
- Muratori L, Ronchi G, Raimondo S, Giacobini-Robecchi MG, Fornaro M, Geuna S. Can regenerated nerve fibers return to normal size? A long-term post-traumatic study of the rat median nerve crush injury model. Microsurgery. 2012;32:383-7.
- Keilhoff G, Goihl A, Langnase K, Fansa H, Wolf G. Transdifferentiation of mesenchymal stem cells into Schwann cell-like myelinating cells. Eur. J. Cell Biol. 2006;85:11–24.
- Ladak A, Olson J, Tredget EE, Gordon T. Differentiation of mesenchymal stem cells to support peripheral nerve regeneration in a rat model. Exp Neurol. 2011;228:242-52.
- Mantovani C, Mahay D, Kingham M, Terenghi G, Shawcross SG, Wiberg M. Bone marrow- and adipose-derived stem cells show expression of myelin mRNAs and proteins. Regen Med. 2010 ;5:403-10.
- Navarro X, Vivó M, Valero-Cabré A. Neural plasticity after peripheral nerve injury and regeneration. Prog Neurobiol. 2007;82:163-201.
- Li GR, Deng XL, Sun H, Chung SS, Tse HF, Lau CP. Ion channels in mesenchymal stem cells from rat bone marrow. Stem Cells. 2006;24:1519-28.
- Liu J, Song L, Jiang C, Liu Y, George J, Ye H et al. Electrophysiological properties and synaptic function of mesenchymal stem cells during neurogenic differentiation - a mini-review. Int J Artif Organs. 2012;35:323-37.
- Pan HC, Yang DY, Chiu YT, Lai SZ, Wang YC, Chang MH et al. Enhanced regeneration in injured sciatic nerve by human amniotic mesenchymal stem cell. J Clin Neurosci. 2006;13:570-5.
- Matsumoto K, Ohnishi K, Kiyotani T, Sekine T, Ueda H, Nakamura T et al. Peripheral nerve regeneration across an 80-mm gap bridged by a polyglycolic acid (PGA)-collagen tube filled with laminin-coated collagen fibers: a histological and electrophysiological evaluation of regenerated nerves. Brain Res. 2000;868:315-28.
- Sakar M, Korkusuz P, Demirbilek M, Cetinkaya DU, Arslan S, Denkbaş EB et al. The effect of poly(3-hydroxybutyrate-co-- hydroxyhexanoate) (PHBHHx) and human mesenchymal stem cell (hMSC) on axonal regeneration in experimental sciatic nerve damage. Int J Neurosci. 2014 ;124:685-96.
- Raisi A1, Azizi S, Delirezh N, Heshmatian B, Farshid AA, Amini K. The mesenchymal stem cell-derived microvesicles enhance sciatic nerve regeneration in rat: a novel approach in peripheral nerve cell therapy. J Trauma Acute Care Surg. 2014;76:991-7.