The Presence of Neural Stem Cells and Changes in Stem Cell-Like Activity With Age in Mouse Spiral Ganglion Cells In Vivo and In Vitro

Abstract

ObjectivesSpiral ganglion neurons (SGNs) include potential endogenous progenitor populations for the regeneration of the peripheral auditory system. However, whether these populations are present in adult mice is largely unknown. We examined the presence and characteristics of SGN-neural stem cells (NSCs) in mice as a function of age.MethodsThe expression of Nestin and Ki67 was examined in sequentially dissected cochlear modiolar tissues from mice of different ages (from postnatal day to 24 weeks) and the sphere-forming populations from the SGNs were isolated and differentiated into different cell types.ResultsThere were significant decreases in Nestin and Ki67 double-positive mitotic progenitor cells in vivo with increasing mouse age. The SGNs formed spheres exhibiting self-renewing activity and multipotent capacity, which were seen in NSCs and were capable of differentiating into neuron and glial cell types. The SGN spheres derived from mice at an early age (postnatal day or 2 weeks) contained more mitotic stem cells than those from mice at a late age.Conclusion.Our findings showed the presence of self-renewing and proliferative subtypes of SGN-NSCs which might serve as a promising source for the regeneration of auditory neurons even in adult mice.

Intrinsically Self-renewing Neuroprogenitors From the A/J Mouse Spiral Ganglion as Virtually Unlimited Source of Mature Auditory Neurons

“…Interestingly, both types I and II neural markers, together with glial cell markers, were induced in the differentiated population, demonstrating that phoenix neuroprogenitors are able to reproduce the cellular diversity present in the spiral ganglia (Petitpré et al, 2018;Shrestha et al, 2018;Sun et al, 2018). Note that even after many passages, a significant proportion of the phoenix progenitors differentiated toward glial cells, expressing GFAP (Figures 4C, 5J), including both Schwann (S100, PLP1) and satellite glial cells (glutamine synthetase; Figure 6), a feature previously observed for SGN progenitors from other mouse strains (Oshima et al, 2007;Martinez-Monedero et al, 2008;Diensthuber et al, 2014;McLean et al, 2016;Moon et al, 2018). Whether the glial cells and neurons are originating from a distinct progenitor subtype in the phoenix neurosphere culture remains to be investigated.…”

“…Yet, it is difficult to understand why auditory neuroprogenitors from the A/J mouse strain exhibit such high self-renewal ability compared to previously described models. In mice, proliferation of SGN progenitors is typically observed during the first postnatal week, but rapidly decreases with age to virtually no regeneration in adults (Oshima et al, 2007;Moon et al, 2018;Senn et al, 2020). The failure of the adult inner ear to regenerate following injury might be explained by the low intrinsic self-renewal ability of mammalian auditory neuroprogenitors.…”

“…In contrast, the mature mammalian cochlea lacks the capacity for efficient regeneration (Warchol et al, 1993). Inner ear progenitor cells are present in mammals; however, their number rapidly decreases with age (Oshima et al, 2007;Moon et al, 2018).…”

WNT Activation and TGFβ-Smad Inhibition Potentiate Stemness of Mammalian Auditory Neuroprogenitors for High-Throughput Generation of Functional Auditory Neurons In Vitro

“…However, common to all discoveries in the field of auditory neuroregeneration is the fact that mammalian cochlear progenitors retain only a minimal regenerative potential into adulthood and that inner ear progenitors reach senescence after two to five passages in sphere-forming suspension-culture assays [ 15 ]. This regenerative potential is mainly observed during the first post-natal week in the mouse, however, rapidly declines with age [ 16 , 17 ]. The reason of this early senescence is still poorly understood, and overcoming this barrier could have major consequences for the development of future regenerative therapies.…”