Interplay of Proliferation and Proapoptotic and Antiapoptotic Factors Is Revealed in the Early Human Inner Ear Development

Hypothesis Spatiotemporal interplay of factors controlling proliferation, differentiation and apoptosis within the developing human inner ear is essential for labyrinth morphogenesis and development of vestibular and cochlear functions. Background Studies on the early human inner ear development are scarce and insufficient. Methods The immunolocalization of Ki-67, Bcl-2, caspase-3, and IGF-1 was analyzed in 6 human inner ears, 5 to 10 gestational weeks old. Statistical data were analyzed using the Kruskal-Wallis test. Results During the analyzed period, the otocyst has transformed into cochlear duct and saccule ventrally and semicircular canals and utricle dorsally. Initial differentiation of sensorineural fields characterized organ of Corti, maculae, and cristae ampullares. Intense (50%) and evenly distributed proliferation Ki-67 in the otocyst decreased to 24% to 30% and became spatially restricted within the membranous labyrinth epithelium. Simultaneously, expression of antiapoptotic Bcl-2 protein increased in sensorineural fields of organ of Corti, macula, and crista ampullaris. Throughout the investigated period, apoptotic caspase-3 positive cells were mainly distributed at the luminal and basal surfaces of labyrinth epithelium. An inhibitor of apoptosis IGF-1 co-expressed with Bcl-2 and increased in the sensorineural fields with advancing development. Conclusion The described expression pattern indicates roles for cell proliferation in the growth of the inner ear and Bcl-2 in differentiation of sensorineural fields and protection from apoptosis. Both IGF-1-and caspase-3-mediated apoptosis seem to contribute to proper morphogenesis, differentiation, and innervations of sensorineural fields within the cochlea, semicircular canals, saccule, and utricle. Alterations in spatiotemporal interplay of investigated factors might lead to disturbances of vestibular and cochlear function.