SERUM 25-HYDROXYVITAMIN D LEVELS IN PATIENTS WITH PROGRESSIVE SENSORINEURAL HEARING LOSS
DOI:
https://doi.org/10.37219/xqh9bk48Keywords:
embryonic neuronal cells, gentamicin ototoxicity, inner ear, auditory nerve, electron microscopy, remyelination, lemmocytesAbstract
Abstract
Background. Sensorineural hearing loss is a polyetiological pathology with no effective treatment methods currently available. Cell therapy opens new frontiers for cochleovestibular regeneration; however, the ultrastructural mechanisms of this process remain insufficiently understood.
Objective. To investigate the characteristics of ultrastructural changes and evaluate the regenerative potential of embryonic neural cells (ENCs) via intratympanic and suboccipital administration in animals with modeled aminoglycoside ototoxicity using transmission electron microscopy (TEM).
Materials and Methods. The experiment was conducted on 30 guinea pigs weighing 500–900 g, divided into 6 groups. Ototoxicity was induced by intramuscular injection of gentamicin sulfate (100 mg/kg, 14 days). ENC suspension (2×10⁶ cells in 0.5 mL) was administered either intratympanically or suboccipitally on day 1 or day 15. Hearing function was assessed via auditory brainstem response (ABR) recording. Inner ear and auditory nerve tissues were examined using TEM.
Results. ENC transplantation into healthy animals confirmed its safety and biocompatibility. The administration of ENCs on day 1 demonstrated a pronounced preventive neuroprotective effect. When ENCs were injected on day 15 post-gentamicin course, the suboccipital route was found to provide active transendothelial migration of cells into the stria vascularis, enhanced vascularization, rapid resorption of myelin lipoprotein degradation products, and active mitochondriogenesis in lemmocytes. The intratympanic route verified a paracrine effect, manifested by the normalization of myelin sheath lamellae, mesaxon formation, stabilization of the axoplasm cytoskeleton (neurotubules), and preservation of afferent axosomatic synapses.
Conclusions. ENC transplantation effectively stimulates the reparative regeneration of damaged inner ear and auditory nerve ultrastructures. The suboccipital route is pathomorphologically more effective for direct cell integration, whereas the intratympanic initiation of regeneration is primarily mediated by paracrine mechanisms.
References
1. Magomedov MM. [Use of fetal tissue in otolaryngology. Analysis of problem and future]. Vestn Otorinolaringol. 1998;(2):16-23. [Russian].
2. Magomedov MM. [The use of fetal tissues in the therapy of chronic sensorineural hearing loss]. In: Proceedings of the International Scientific Conference dedicated to the 75th anniversary of the Department of Otolaryngology of Dnipropetrovsk and clinics of medical academies; 1997; Dnipropetrovsk. p. 140-141. [Russian].
3. Semenova VV, Tsimbalyuk VI, Pichkur LD, Staino LP. [Cytostructural comparative evaluation of human embryonic neural tissue growth during cultivation using various storage methods]. Ukr Neurosurg J. 2008;(4):68-71. [Russian].
4. Sapizhak I, Timen G, Semenova V, Staino L. Influence of embryonic neuronal cells on the structures of the internal auricles in experimental ototoxicosis (morphological assessment). Ukr Neurosurg J. 2017;(4):32-37. doi: 10.25305/unj.115236.
5. Tsimbalyuk VI. [Neurotransplantation]. Likuvannya ta Diagnostika. 2000;(3):15-19. [Ukrainian].
6. Chaikovsky YuV, Deltsova OI, Gerashchenko SB. [Brain stem cells in the postnatal period]. World Med Biol. 2011;7(4):148-153. [Ukrainian].
7. Groves AK. The challenge of hair cell regeneration. Exp Biol Med (Maywood). 2010;235(4):434-446. doi: 10.1258/ebm.2010.009318.
8. Huisman MA, Rivolta MN. Neural crest stem cells and their potential application in a therapy for deafness. Front Biosci (Schol Ed). 2012;4(1):121-132. doi: 10.2741/s254.
9. Kersigo J, Fritzsch B. Inner ear hair cells deteriorate in mice engineered to have no or diminished innervation. Front Aging Neurosci. 2015;7:33. doi: 10.3389/fnagi.2015.00033.
10. Nishimura K, Nakagawa T, Ono K, Ogita H, Sakamoto T, Yamamoto N, et al. Transplantation of mouse induced pluripotent stem cells into the cochlea. Neuroreport. 2009;20(14):1250-1254. doi: 10.1097/WNR.0b013e32832f3f4c.
11. Nakagawa T, Ito J. Cell therapy for inner ear diseases. Curr Pharm Des. 2005;11(9):1203-1207. doi: 10.2174/1381612053507530.
12. Oshikawa M, Ikeda R, Saito T, Nakagawa T, Ito J. Role of neurotrophic factors (BDNF and GDNF) on the survival of neural progenitor cells transplanted into the inner ear. Hear Res. 2004;195(1-2):74-82. doi: 10.1016/j.heares.2004.05.003.
13. Rivolta MN, Li H, Heller S. Generation of inner ear cell types from embryonic stem cells. Methods Mol Biol. 2006;330:71-92. doi: 10.1385/1-59745-028-1:71.
14. Matsui JI, Ogilvie JM, Warchol ME. Inhibition of caspases prevents ototoxic and ongoing hair cell death in the mature central auditory system. J Neurosci. 2003;23(21):7822-7831. doi: 10.1523/JNEUROSCI.23-21-07822.2003.
15. Bas E, Martinez-Monedero R, Corrales CE, Edge AS. Mechanisms of aminoglycoside ototoxicity and targets of hair cell protection. Mol Neurobiol. 2012;46(3):564-577. doi: 10.1007/s12035-012-8302-3.
16. Steffen A, Takebayashi S, Nakagawa T, Iwai K, Ito J. Survival and differentiation of neural stem cells grafted into injured inner ears of mice. Acta Otolaryngol. 2003;123(5):590-595. doi: 10.1080/00016480310001297.
17. Martinez-Monedero R, Corrales CE, Edge AS. Stem cells for the replacement of inner ear neurons and hair cells. Int J Dev Biol. 2007;51(6-7):645-653. doi: 10.1387/ijdb.072346rm.
18. Council of Europe. European Convention for the Protection of Vertebrate Animals Raised for Experimental and Other Scientific Purposes. Strasbourg: Council of Europe; 1986. Treaty Series No.: 123.
