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The effects of mesenchymal stem cells applied during the subacute period in peripheral neuropathy Skip to content Yıl 2024, Cilt: 49 Sayı: 2, 424 – 438, 30.06.2024
Olcay Kıroğlu , Erkan Maytalman , Ares Alizade , Mustafa Emre , Suzan Zorludemir , Fazilet Aksu
https://doi.org/10.17826/cumj.1453906
Öz 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.
Anahtar Kelimeler Mezenkimal kök hücre, periferik nöropati, ağrı.
Etik Beyan 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.
Destekleyen Kurum This study was supported by grants from theCukurova University Scientific Research Projects Unit, project no. TF2011BAP12.
Teşekkür We would like to thank Berk Çelikyürek for his editing contributions.
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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.
The effects of mesenchymal stem cells applied during the subacute period in peripheral neuropathy Yıl 2024, Cilt: 49 Sayı: 2, 424 – 438, 30.06.2024
Olcay Kıroğlu , Erkan Maytalman , Ares Alizade , Mustafa Emre , Suzan Zorludemir , Fazilet Aksu
https://doi.org/10.17826/cumj.1453906
Öz 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.
Anahtar Kelimeler mesenchymal stem cell, peripheric neuropathy, pain
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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. 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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. Toplam 48 adet kaynakça vardır.
Ayrıntılar Birincil Dil İngilizce Konular Periferik Sinir Sistemi Bölüm Araştırma Yazarlar Olcay Kıroğlu ÇUKUROVA ÜNİVERSİTESİ, TIP FAKÜLTESİ 0000-0003-3182-2122 Türkiye
Erkan Maytalman ALANYA ALAADDIN KEYKUBAT UNIVERSITY, FACULTY OF MEDICINE 0000-0001-5284-7439 Türkiye
Ares Alizade YUZUNCU YIL UNIVERSITY, FACULTY OF MEDİCİNE, DEPARTMAN OF PHARMACOLOGY 0000-0003-0334-8152 Türkiye
Mustafa Emre CUKUROVA UNIVERSITY, FACULTY OF MEDICINE 0000-0001-9897-6674 Türkiye
Suzan Zorludemir CUKUROVA UNIVERSITY, FACULTY OF MEDICINE 0000-0001-9833-4938 Türkiye
Fazilet Aksu CUKUROVA UNIVERSITY, FACULTY OF MEDICINE 0000-0003-3585-2599 Türkiye
Yayımlanma Tarihi 30 Haziran 2024 Gönderilme Tarihi 16 Mart 2024 Kabul Tarihi 11 Mayıs 2024 Yayımlandığı Sayı Yıl 2024 Cilt: 49 Sayı: 2
Kaynak Göster MLA Kıroğlu, Olcay vd. “The Effects of Mesenchymal Stem Cells Applied During the Subacute Period in Peripheral Neuropathy”. Cukurova Medical Journal, c. 49, sy. 2, 2024, ss. 424-38, doi:10.17826/cumj.1453906.
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