天美传媒

Genetics, ageing, and exposure to noise or ototoxic chemicals are the main causes of HC and SGN loss. Generating new functioning cells to replace the damaged sensory cells is one potentially possible technique to restore auditory physiology. Significant attempts have been undertaken in recent years to obtain HCs and SGNs from inner ear stem/progenitor cells, embryonic stem cells (ESCs), and induced pluripotent stem cells since stem cells have the ability to self-renew and differentiate into numerous lineages. The existence of stem/progenitor cells, particularly in the inner ear, is widely acknowledged [1].

Structure and Development

These cells, which are generally referred to as cochlear stem/ progenitor cells, can give rise to both HCs and supporting cells (SCs), in particular in the organ of Corti. According to studies, the spiral ganglion region contains cells with stem cell characteristics as well. These cells, which are known as spiral ganglion-derived neural stem cells, can differentiate into neurons. As sources of HCs and SGNs, ESCs/iPSCs and other foreign stem cells are also options [2]. The search for effective therapeutic approaches for hearing loss must begin with the identification and growth of a renewable source of stem/ progenitor cells and the induction of these cells to differentiate into HCs. In this review, we emphasise the traits of Mammalian inner ear stem/progenitor cells and their utilisation to replenish or swap out the cochlear sensory HCs and SGNs. The scala vestibuli, scala tympani, and cochlear duct are the three chambers that make up the mammalian cochlea. In the cochlear duct, the organ of Corti detects, amplifies, and converts mechanical sound waves into electrical impulses that are sent to the SGNs via neurotransmitters. One row of inner HCs, three rows of outer HCs, plus a number of underlying non-sensory SC subtypes, including Deiters’ cells, pillar cells, inner phalangeal/border cells, and Hensen’s cells, make up the organ of Corti [3]. Based on whether they are connected to inner or outer HCs, the SGNs are split into two kinds. While Type II SGNs are unmyelinated and receive input from numerous different outside types, Type I SGNs are myelinated bipolar neurons that link with an inner HC by a single synapse. In addition, new research using single-cell RNA sequence analysis has revealed three distinct subclasses of type I SGNs. The otic placode, a thickened ectoderm next to the hind brain, is where almost all of the cochlea’s structures originate [4].

The earliest markers during this time appear to be Pax8, Pax2, Sox2, and Sox9. At embryonic day 9.5 in mice, the placodal ectoderm invades to form a pit, gradually deepens into a cup, and then eventually shuts to form the otocyst. At E9, the neuroblasts that surround the otocyst start to delaminate eventually were forming the spiral ganglion. The expression of neurogenin1 in these delaminating cells distinguishes them, and they begin to undergo postmitotic transformation at the base and reaching the summit. Then, differentiation proceeds in an apical to basal gradient into the different cell types of the organ of Corti. The restricted expression of Myosin 6 and Myosin 7a in HCs appears to be the second earliest HC marker after Atoh1.Sox9 expression localises to SCs, whereas Sox2 stays in SCs but is no longer present in HCs [5-7]. Up to postnatal day (P) 12, the SGNs create synapses with the HCs. Neonatal cochlear tissue can be used to isolate stem/progenitor cells for the inner ear. Most studies have confirmed that stem/progenitor cells of the organ of Corti after birth can be differentiated into SCs and HCs. Several reports using culture systems have demonstrated the presence of potential cochlear stem/progenitor cells in the postnatal cochlea that have the capacity for sphere formation. Even while it may be debatable whether certain SCs with proliferation and differentiation capacity in the postnatal cochlea can actually be referred to as “stem cells,” they can still be thought of as a progenitor cell population with lineage differentiation potential. The adult mouse utricle, an organ in the inner ear that was where the first evidence of sphere creation from inner ear cells was found maintaining balance; In that study, they labelled mitotically active cells with BrdU, and X-gal histochemistry during the creation of the spheres established that the spheres originated from individual sensory epithelium cells. In addition to expressing Pax-2, BMP-4, and BMP-7 transcripts, these spheres were also capable of differentiating into HC-like cells with bundle-like structures that expressed the HC markers Myosin 7a and Espin [8].

Result

The lower epithelial ridge epithelia of the neonatal rat cochlea have also yielded cell lines with characteristics resembling those of cochlear stem cells. Primitive Hensen’s, Claudius’, and other non-HC epithelial cells are produced after birth by cells of the smaller epithelial ridge. In the presence of, Wang et al. grew spheres made from immature cochlear basilar membrane cells. Basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) [9]. The sphere cells contained the progenitor cell markers Otx2, BMP4, BMP7, and Islet1, and the spheres developed into cells that expressed HC and SC markers. There are fewer reports on stem/progenitor cells from the mature organ of Corti than there are for stem cells found in the adult utricle. Progenitor cells were observed in the cochlea of newborn mice in two investigations, and they discovered a rapid decline in their potential to form spheres over the first three postnatal weeks. According to a recent study, the adult human cochlea may contain progenitor cells since they were able to observe the production of spheres from adult human cochlea cells and because the adult human cochlea contains there is a distinct group of cells that the stem cell marker Abcg2-positive. Although Abcg2- positive cells from the neonatal cochlea isolated by fluorescenceactivated cell sorting are capable of developing into HC-like cells and can multiply into spheres, more research is necessary to prove Abcg2 as a marker of adult inner ear stem cells. However, adult colony expansion was much weaker than that seen for the colonies from neonatal mouse Lgr5-positive SCs, and only a few cells were seen in each adult colony. Another recent study demonstrated that a combination of growth factors and compounds can promote adult mouse Lgr5-positive SCs and human cochlear cells to generate clonal colonies in 3D culture [10].

Discussion

Although colonies grown in differentiation medium that contains a Wnt activator and a Notch inhibitor produce cells that positively stain for the HC marker Myosin 7a, and Adult mammalian cochlear stem/progenitor cell research has new hope as a result of this. However, further research is needed to confirm the existence of adult cochlear stem/progenitor cells and to fully comprehend their properties. In both mice and humans, a number of proteins, including Lgr5, Lgr6, and EPCAM, have been identified as markers of cochlear progenitor cells. Post-mitotic SCs isolated from post-natal mouse cochlea that are p27Kip1 and p75NGFR-positive continue to divide and differentiate into new HCs in culture [11]. While p75NGFR-positive cells are the SC subpopulations of pillar cells and Hensen’s cells, p27Kip1 is expressed in all SC types. Furthermore, compared to other cochlear epithelial cells, p75NGFR-positive SCs are enriched for the ability to differentiate into HC. Showed that Abcg2-positive cells grow and form significant floating colonies in the presence of EGF and bFGF, and the resultant spheres express HC and SC markers under differentiation conditions, demonstrating stem/progenitor cell characteristics. Expression of ABCG2 in Cochlear Epithelium only affects SCs, such as Deiters’, Hensen’s, borders, and inner phalangeal cells. Recent research has demonstrated that Lgr5-positive SCs can function as progenitor cells in the mammalian cochlea and that these cells have the ability to regenerate throughout the early postnatal stage. Several organs, including the gut, have been discovered to express the stem cell marker Lgr5. liver, stomach, taste buds, hair follicles, and mammary gland. Lgr5 expression begins in the floor epithelium of the mammalian cochlea, where it is also co-expressed with the possessory markers Sox2, Jagged1, and p27Kip1. Lgr5 expression is only found in some subsets of SCs at later stages, and in the adult organ of Corti, only the third row of Deiters’ cells exhibits observable Lgr5 expression.

Conclusion

Reported that Lgr6-positive progenitor cells had a much better capacity to give rise to HCs than Lgr5-positive progenitor cells, however Lgr6-positive HC progenitors showed a lesser capacity for growth than Lgr5-positive progenitor cells. In a lineage-tracing experiment, Lgr5- positive progenitor cells from the sensory epithelia gave rise to HC-like cells and SCs, but not neurons [12]. This was discovered by breeding Lgr5-EGFP-IRES-CreER mice with floxed-tdTomato mice. In a recent investigation, foetal human postmitotic HC progenitors were identified using the cochlear prosensory domain markers EPCAM and CD271. In Matrigel, cultured EPCAM/CD271 double-positive cells allowed for the formation of epithelial colonies that express the stem cell markers SOX9, SOX2, and FBXO2, but not Lgr5. In situ hybridization assays revealed that Lgr5 mRNA was undetectable in the prosensory domain region of all cochlear turns at postnatal week 9 (W9). They similarly displayed no detectable expression at postnatal week 8 (W8) and only weak Lgr5 immunostaining at W10 and W12. These studies collectively imply that stem/progenitor cells are present in the postnatal mammalian cochlea and may endure into adulthood.

Conflict of Interest

None

Acknowledgement

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