Bone marrow-derived mesenchymal stem cells mitigate colistin-induced cochlear ototoxicity: an experimental study
Öz
Purpose: This study investigates the therapeutic potential of mesenchymal stem cells in colistin-induced hearing loss.
Materials and Methods: Forty Wistar albino rats were divided into four groups (n=10): Control (36 mg/kg/day intraperitoneal (ip) saline for 7 days), Colistin (36 mg/kg/day ip for 7 days), Mesenchymal stem cell group (MSC) (5×10⁶ MSC via tail vein), and Colistin+Mesenchymal stem cell group (Col+MSC) (colistin for 7 days, then MSC 1 hour after final dose). After the experiment, cochlear tissues were extracted, fixed, decalcified, embedded in paraffin, sectioned (5µm), and stained with Masson’s trichrome (MT) for histological evaluation under light microscopy.
Results: Colistin caused marked structural damage, especially in the basal and medial cochlear turns. In the apical and medial regions, stria vascularis thickness was significantly lower in the colistin group (10.64±1.90, 11.54±2.32) than in the control (14.12±2.03, 15.43±2.26) and MSC (13.91±1.49, 14.53±1.80) groups. Significant intergroup differences were also noted in the basal turn. Inner hair cell lengths were similar apically but significantly reduced in the colistin (30.73±4.28) and Col+MSC (31.06±6.96) groups medially. Outer hair cell lengths were significantly reduced in the colistin group in both apical (32.23±8.32) and basal (18.32±2.47) regions. Tectorial membrane thickness in the basal turn was significantly reduced in all treatment groups compared to the control (17.64±5.41). Based on Freitas et al.'s criteria, the colistin group showed significantly higher histopathological damage scores in all regions compared to the control and MSC groups. The Col+MSC group showed improved morphology and lower scores, though some differences lacked statistical significance.
Conclusion: MSCs significantly alleviated colistin-induced ototoxicity, indicating their protective and therapeutic potential in inner ear injury.
Anahtar Kelimeler
Colistin; ototoxicity, mesenchymal stem cell, cochlea, organ of corti
Etik Beyan
Number 24/234- Approval date 05/12/2024
Destekleyen Kurum
This study was supported by the Erciyes University Scientific Research Projects
Proje Numarası
TSA-2021-11331
Kaynakça
- Park YH. Stem cell therapy for sensorineural hearing loss, still alive? J Audiol Otol. 2015;19:63-7.
- Kwa A, Kasiakou SK, Tam VH, Falagas ME. Polymyxin B: similarities to and differences from colistin (polymyxin E). Expert Rev Anti Infect Ther. 2007;5:811-21.
- Leong KW, Ong S, Chee HL, Lee W, Kwa AL. Hypersensitivity pneumonitis due to high-dose colistin aerosol therapy. Int J Infect Dis. 2010;14:e1018-9.
- Levin AS, Barone AA, Penço J, Santos MV, Marinho IS, Arruda EA et al. Intravenous colistin as therapy for nosocomial infections caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii. Clin Infect Dis. 1999;28:1008-11.
- Li J, Turnidge J, Milne R, Nation RL, Coulthard K. In vitro pharmacodynamic properties of colistin and colistin methanesulfonate against Pseudomonas aeruginosa isolates from patients with cystic fibrosis. Antimicrob Agents Chemother. 2001;45:781-5.
- Markantonis SL, Markou N, Fousteri M, Sakellaridis N, Karatzas S, Alamanos I et al. Penetration of colistin into cerebrospinal fluid. Antimicrob Agents Chemother. 2009;53:4907-10.
- Bergen PJ, Landersdorfer CB, Zhang J, Zhao M, Lee HJ, Nation RL et al. Pharmacokinetics and pharmacodynamics of 'old' polymyxins: what is new? Diagn Microbiol Infect Dis. 2012;74:213-23.
- Giamarellou H. Multidrug-resistant Gram-negative bacteria: how to treat and for how long. Int J Antimicrob Agents. 2010;36:S50-4.
- Lim LM, Ly N, Anderson D, Yang JC, Macander L, Jarkowski A 3rd et al. Resurgence of colistin: a review of resistance, toxicity, pharmacodynamics, and dosing. Pharmacotherapy. 2010;30:1279-91.
- Boisson M, Gregoire N, Couet W, Mimoz O. Colistin in critically ill patients. Minerva Anestesiol. 2013;79:200-8.
- Yalvaç ME, Yilmaz A, Mercan D, Aydin S, Dogan A, Arslan A et al. Differentiation and neuro-protective properties of immortalized human tooth germ stem cells. Neurochem Res. 2011;36:2227-35.
- Mangir N, Akbal C, Tarcan T, Simsek F, Turkeri L. Mesenchymal stem cell therapy in the treatment of erectile dysfunction: autologous or allogeneic cell sources? Int J Urol. 2014;21:1280-5.
- Weiss ARR, Dahlke MH. Immunomodulation by mesenchymal stem cells (MSCs): mechanisms of action of living, apoptotic, and dead MSCs. Front Immunol. 2019;10:1191.
- Balcioglu E, Gur MF, Gur HE, Bilgici P, Kankılıç T. Histological structure of Nannospalax xanthodon cochlea tissue. Biologia. 2021;76:2543–8.
- Balcıoğlu E, Bilgici P, Yalçın B, Yay AH, Bolat D, Ceyhan A et al. Histological examination of structural changes in the cochlear canal. Kulak Burun Boğaz Uygulamaları. 2021;9:12-7.
- Yalçın B, Balcıoğlu E, Yay A, Önder GÖ, Bilgici B, Somdaş MA. Investigation of the histological structure of the cochlea and the corti under light and electron microscopes. Kulak Burun Boğaz Uygulamaları. 2020;8:160-4.
- Raphael Y, Altschuler RA. Structure and innervation of the cochlea. Brain Res Bull. 2003;60:397-422.
- Freitas M, Castro BG, De CJ, Gomes R, Barreto MM, Albuquerque RR. Light microscopy study of cisplatin-induced ototoxicity in rats. J Laryngol Otol. 2009;123:590-7.
- Waissbluth S, Peleva E, Daniel SJ. Platinum-induced ototoxicity: a review of prevailing ototoxicity criteria. Eur Arch Otorhinolaryngol. 2017;274:1187-96.
- Yang L, Cao J, Du Y, Zhang X, Hong W, Peng B et al. Initial IL-10 production dominates the mesenchymal stem cell scaffold therapy in spinal cord injury. Theranostics. 2024;14:879-91.
- Kawatani K, Omana Suarez G, Perkerson RB 3rd, Parent EE, Nambara T, Knight JA et al. Human iPSC-derived MSCs induce neurotrophic effects and improve metabolic activity in acute neuronal injury models. J Neurosci. 2025;45:e0606242024.
- Falagas ME, Kasiakou SK, Michalopoulos A. Polymyxins: a word of caution for prudent use of valuable "old antibiotics". Infect Control Hosp Epidemiol. 2006;27:995.
- Shubnikova EV, Velts NY. Ototoxicity of aminoglycosides: the modern concepts. Meditsinskiy Sovet. 2022;67:79-90.
- Ruan Q, Ao H, He J, Chen Z, Yu Z, Zhang R et al. Topographic and quantitative evaluation of gentamicin-induced damage to peripheral innervation of mouse cochleae. Neurotoxicology.2014;40:86-96.
- Akeel MA. Ultrastructural analysis and ABR alterations in the cochlear hair-cells following aminoglycosides administration in guinea pig. Global Journal of Otolaryngology. 2018;15:GJO.MS.ID.555916.
- Hodge SE, Lopez IA, Ishiyama G, Ishiyama A. Cisplatin ototoxicity histopathology. Laryngoscope Investig Otolaryngol. 2021;6:852-56.
- Kavanagh KR, Parham K, Schoem SR. Auditory function after a prolonged course of ciprofloxacin-dexamethasone otic suspension in a murine model. Arch Otolaryngol Head Neck Surg. 2009;135:238-41.
- Adeyemo AA, Adedokun B, Adeolu J, Akinyemi JO, Omotade OO, Oluwatosin OM. Re-telling the story of aminoglycoside ototoxicity: tales from sub-Saharan Africa. Front Neurol. 202428;15.
- Kros CJ, Steyger PS. Aminoglycoside- and cisplatin-induced ototoxicity: mechanisms and otoprotective strategies. Cold Spring Harb Perspect Med. 2019;9:a033548.
- Smith CR, Lipsky JJ, Laskin OL, Hellmann DB, Mellits ED, Longstreth J et al. Double-blind comparison of the nephrotoxicity and auditory toxicity of gentamicin and tobramycin.N Engl J Med.1980;302:1106-9.
- Shafik AG, Elkabarity RH, Thabet MT, Soliman NB, Kalleny NK. Effect of intratympanic dexamethasone administration on cisplatin-induced ototoxicity in adult guinea pigs. Auris Nasus Larynx. 2013;40:51-60.
- Prasad KN, Bondy SC. Increased oxidative stress, inflammation, and glutamate: Potential preventive and therapeutic targets for hearing disorders. Mech Ageing Dev. 2020;185:111191.
- Koo JW, Quintanilla-Dieck L, Jiang M, Liu J, Urdang ZD, Allensworth JJ et al. Endotoxemia-mediated inflammation potentiates aminoglycoside-induced ototoxicity. Sci Transl Med. 2015;7:298ra118.
- Probst R, Harris FP, Hauser R. Clinical monitoring using otoacoustic emissions. Br J Audiol. 1993;27:85-90.
- Hu Z, Ulfendahl M. The potential of stem cells for the restoration of auditory function in humans. Regen Med. 2013;8:309-18.
- Santaolalla F, Salvador C, Martínez A, Sánchez JM, Del Rey AS. Inner ear hair cell regeneration: A look from the past to the future. Neural Regen Res. 2013;8:2284-9.
- Martinez-Monedero R, Oshima K, Heller S, Edge AS. The potential role of endogenous stem cells in the regeneration of the inner ear. Hear Res. 2007;227:48-52.
- Corrales CE, Pan L, Li H, Liberman MC, Heller S, Edge AS. Engraftment and differentiation of embryonic stem cell-derived neural progenitor cells in the cochlear nerve trunk: growth of processes into the organ of Corti. J Neurobiol. 2006;66:1489-500.
- Xu YP, Shan XD, Liu YY, Pu Y, Wang CY, Tao QL et al. Olfactory epithelium neural stem cell implantation restores noise-induced hearing loss in rats. Neurosci Lett. 2016;616:19-25.
- Elbana AM, Abdel-Salam S, Morad GM, Omran AA. Role of endogenous bone marrow stem cells mobilization in repair of damaged ınner ear in rats. Int J Stem Cells. 2015;8:146-54.
Kemik iliği kaynaklı mezenkimal kök hücreler kolistin kaynaklı koklear ototoksisiteyi azaltır: deneysel bir çalışma
Öz
Amaç: Bu çalışma, kolistin kaynaklı işitme kaybında mezenkimal kök hücrelerin (MSC) terapötik potansiyelini araştırmayı amaçlamaktadır.
Gereç ve Yöntem: Kırk Wistar albino sıçan dört gruba ayrıldı (n=10): Kontrol (7 gün boyunca 36 mg/kg/gün intraperitoneal (ip) serum fizyolojik), Kolistin (7 gün boyunca 36 mg/kg/gün ip kolistin), Mezenkimal kök hücre grubu (MSC) (kuyruk veninden 5×10⁶ MSC), ve Kolistin+MSC grubu (Col+MSC) (7 gün boyunca kolistin, son dozdan 1 saat sonra 5×10⁶ MSC). Deney sonunda, koklea dokuları çıkarıldı, fikse edildi, dekalcifiye edildi, parafin bloklara gömüldü, 5 µm kalınlığında kesitler alındı ve Masson’s trikrom (MT) ile boyanarak ışık mikroskobu altında histolojik olarak değerlendirildi.
Bulgular: Kolistin grubu özellikle kokleanın bazal ve medial kıvrımlarında belirgin yapısal hasar gösterdi. Apikal ve medial bölgelerde, stria vaskülaris kalınlığı kolistin grubunda (10.64±1.90, 11.54±2.32) kontrol (14.12±2.03, 15.43±2.26) ve MSC (13.91±1.49, 14.53±1.80) gruplarına göre anlamlı derecede azdı. Bazal kıvrımda da gruplar arasında anlamlı farklılıklar gözlendi. İç tüylü hücrelerin uzunlukları apikalde benzerken, medialde kolistin (30.73±4.28) ve Col+MSC (31.06±6.96) gruplarında anlamlı azalma görüldü. Dış tüylü hücre uzunlukları ise kolistin grubunda hem apikal (32.23±8.32) hem de bazal (18.32±2.47) bölgelerde anlamlı şekilde kısaydı. Bazal kıvrımda, tectorial membran kalınlığı tüm tedavi gruplarında kontrol grubuna (17.64±5.41) kıyasla anlamlı şekilde azaldı. Freitas ve ark. tarafından tanımlanan kriterlere göre, kolistin grubunun tüm bölgelerde histopatolojik hasar skorları kontrol ve MSC gruplarına göre anlamlı olarak daha yüksekti. Col+MSC grubu daha organize morfoloji ve düşük skorlar gösterse de bazı farklılıklar istatistiksel olarak anlamlı değildi.
Sonuç: MSC'ler, kolistin kaynaklı ototoksisiteyi anlamlı derecede hafifleterek iç kulak hasarında koruyucu ve terapötik potansiyele sahip olduklarını göstermektedir.
Anahtar Kelimeler
Kolistin, ototoksisite, mezenkimal kök hücre, koklea, korti organı,
Etik Beyan
Number 24/234- Approval date 05/12/2024
Destekleyen Kurum
Erciyes Üniversitesi Bilimsel Araştırma Projeleri bu çalışmayı finanse etti.
Proje Numarası
TSA-2021-11331
Kaynakça
- Park YH. Stem cell therapy for sensorineural hearing loss, still alive? J Audiol Otol. 2015;19:63-7.
- Kwa A, Kasiakou SK, Tam VH, Falagas ME. Polymyxin B: similarities to and differences from colistin (polymyxin E). Expert Rev Anti Infect Ther. 2007;5:811-21.
- Leong KW, Ong S, Chee HL, Lee W, Kwa AL. Hypersensitivity pneumonitis due to high-dose colistin aerosol therapy. Int J Infect Dis. 2010;14:e1018-9.
- Levin AS, Barone AA, Penço J, Santos MV, Marinho IS, Arruda EA et al. Intravenous colistin as therapy for nosocomial infections caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii. Clin Infect Dis. 1999;28:1008-11.
- Li J, Turnidge J, Milne R, Nation RL, Coulthard K. In vitro pharmacodynamic properties of colistin and colistin methanesulfonate against Pseudomonas aeruginosa isolates from patients with cystic fibrosis. Antimicrob Agents Chemother. 2001;45:781-5.
- Markantonis SL, Markou N, Fousteri M, Sakellaridis N, Karatzas S, Alamanos I et al. Penetration of colistin into cerebrospinal fluid. Antimicrob Agents Chemother. 2009;53:4907-10.
- Bergen PJ, Landersdorfer CB, Zhang J, Zhao M, Lee HJ, Nation RL et al. Pharmacokinetics and pharmacodynamics of 'old' polymyxins: what is new? Diagn Microbiol Infect Dis. 2012;74:213-23.
- Giamarellou H. Multidrug-resistant Gram-negative bacteria: how to treat and for how long. Int J Antimicrob Agents. 2010;36:S50-4.
- Lim LM, Ly N, Anderson D, Yang JC, Macander L, Jarkowski A 3rd et al. Resurgence of colistin: a review of resistance, toxicity, pharmacodynamics, and dosing. Pharmacotherapy. 2010;30:1279-91.
- Boisson M, Gregoire N, Couet W, Mimoz O. Colistin in critically ill patients. Minerva Anestesiol. 2013;79:200-8.
- Yalvaç ME, Yilmaz A, Mercan D, Aydin S, Dogan A, Arslan A et al. Differentiation and neuro-protective properties of immortalized human tooth germ stem cells. Neurochem Res. 2011;36:2227-35.
- Mangir N, Akbal C, Tarcan T, Simsek F, Turkeri L. Mesenchymal stem cell therapy in the treatment of erectile dysfunction: autologous or allogeneic cell sources? Int J Urol. 2014;21:1280-5.
- Weiss ARR, Dahlke MH. Immunomodulation by mesenchymal stem cells (MSCs): mechanisms of action of living, apoptotic, and dead MSCs. Front Immunol. 2019;10:1191.
- Balcioglu E, Gur MF, Gur HE, Bilgici P, Kankılıç T. Histological structure of Nannospalax xanthodon cochlea tissue. Biologia. 2021;76:2543–8.
- Balcıoğlu E, Bilgici P, Yalçın B, Yay AH, Bolat D, Ceyhan A et al. Histological examination of structural changes in the cochlear canal. Kulak Burun Boğaz Uygulamaları. 2021;9:12-7.
- Yalçın B, Balcıoğlu E, Yay A, Önder GÖ, Bilgici B, Somdaş MA. Investigation of the histological structure of the cochlea and the corti under light and electron microscopes. Kulak Burun Boğaz Uygulamaları. 2020;8:160-4.
- Raphael Y, Altschuler RA. Structure and innervation of the cochlea. Brain Res Bull. 2003;60:397-422.
- Freitas M, Castro BG, De CJ, Gomes R, Barreto MM, Albuquerque RR. Light microscopy study of cisplatin-induced ototoxicity in rats. J Laryngol Otol. 2009;123:590-7.
- Waissbluth S, Peleva E, Daniel SJ. Platinum-induced ototoxicity: a review of prevailing ototoxicity criteria. Eur Arch Otorhinolaryngol. 2017;274:1187-96.
- Yang L, Cao J, Du Y, Zhang X, Hong W, Peng B et al. Initial IL-10 production dominates the mesenchymal stem cell scaffold therapy in spinal cord injury. Theranostics. 2024;14:879-91.
- Kawatani K, Omana Suarez G, Perkerson RB 3rd, Parent EE, Nambara T, Knight JA et al. Human iPSC-derived MSCs induce neurotrophic effects and improve metabolic activity in acute neuronal injury models. J Neurosci. 2025;45:e0606242024.
- Falagas ME, Kasiakou SK, Michalopoulos A. Polymyxins: a word of caution for prudent use of valuable "old antibiotics". Infect Control Hosp Epidemiol. 2006;27:995.
- Shubnikova EV, Velts NY. Ototoxicity of aminoglycosides: the modern concepts. Meditsinskiy Sovet. 2022;67:79-90.
- Ruan Q, Ao H, He J, Chen Z, Yu Z, Zhang R et al. Topographic and quantitative evaluation of gentamicin-induced damage to peripheral innervation of mouse cochleae. Neurotoxicology.2014;40:86-96.
- Akeel MA. Ultrastructural analysis and ABR alterations in the cochlear hair-cells following aminoglycosides administration in guinea pig. Global Journal of Otolaryngology. 2018;15:GJO.MS.ID.555916.
- Hodge SE, Lopez IA, Ishiyama G, Ishiyama A. Cisplatin ototoxicity histopathology. Laryngoscope Investig Otolaryngol. 2021;6:852-56.
- Kavanagh KR, Parham K, Schoem SR. Auditory function after a prolonged course of ciprofloxacin-dexamethasone otic suspension in a murine model. Arch Otolaryngol Head Neck Surg. 2009;135:238-41.
- Adeyemo AA, Adedokun B, Adeolu J, Akinyemi JO, Omotade OO, Oluwatosin OM. Re-telling the story of aminoglycoside ototoxicity: tales from sub-Saharan Africa. Front Neurol. 202428;15.
- Kros CJ, Steyger PS. Aminoglycoside- and cisplatin-induced ototoxicity: mechanisms and otoprotective strategies. Cold Spring Harb Perspect Med. 2019;9:a033548.
- Smith CR, Lipsky JJ, Laskin OL, Hellmann DB, Mellits ED, Longstreth J et al. Double-blind comparison of the nephrotoxicity and auditory toxicity of gentamicin and tobramycin.N Engl J Med.1980;302:1106-9.
- Shafik AG, Elkabarity RH, Thabet MT, Soliman NB, Kalleny NK. Effect of intratympanic dexamethasone administration on cisplatin-induced ototoxicity in adult guinea pigs. Auris Nasus Larynx. 2013;40:51-60.
- Prasad KN, Bondy SC. Increased oxidative stress, inflammation, and glutamate: Potential preventive and therapeutic targets for hearing disorders. Mech Ageing Dev. 2020;185:111191.
- Koo JW, Quintanilla-Dieck L, Jiang M, Liu J, Urdang ZD, Allensworth JJ et al. Endotoxemia-mediated inflammation potentiates aminoglycoside-induced ototoxicity. Sci Transl Med. 2015;7:298ra118.
- Probst R, Harris FP, Hauser R. Clinical monitoring using otoacoustic emissions. Br J Audiol. 1993;27:85-90.
- Hu Z, Ulfendahl M. The potential of stem cells for the restoration of auditory function in humans. Regen Med. 2013;8:309-18.
- Santaolalla F, Salvador C, Martínez A, Sánchez JM, Del Rey AS. Inner ear hair cell regeneration: A look from the past to the future. Neural Regen Res. 2013;8:2284-9.
- Martinez-Monedero R, Oshima K, Heller S, Edge AS. The potential role of endogenous stem cells in the regeneration of the inner ear. Hear Res. 2007;227:48-52.
- Corrales CE, Pan L, Li H, Liberman MC, Heller S, Edge AS. Engraftment and differentiation of embryonic stem cell-derived neural progenitor cells in the cochlear nerve trunk: growth of processes into the organ of Corti. J Neurobiol. 2006;66:1489-500.
- Xu YP, Shan XD, Liu YY, Pu Y, Wang CY, Tao QL et al. Olfactory epithelium neural stem cell implantation restores noise-induced hearing loss in rats. Neurosci Lett. 2016;616:19-25.
- Elbana AM, Abdel-Salam S, Morad GM, Omran AA. Role of endogenous bone marrow stem cells mobilization in repair of damaged ınner ear in rats. Int J Stem Cells. 2015;8:146-54.
Ayrıntılar
| Birincil Dil | İngilizce |
|---|---|
| Konular | Anesteziyoloji, Yoğun Bakım |
| Bölüm | Araştırma |
| Yazarlar | |
| Proje Numarası | TSA-2021-11331 |
| Yayımlanma Tarihi | 30 Haziran 2025 |
| Gönderilme Tarihi | 16 Ocak 2025 |
| Kabul Tarihi | 5 Mayıs 2025 |
| Yayımlandığı Sayı | Yıl 2025 Cilt: 50 Sayı: 2 |
