AAV-Net1 facilitates the trans-differentiation of supporting cells into hair cells in the murine cochlea

Kremen1 regulates the regenerative capacity of support cells and mechanosensory hair cells in the zebrafish lateral line

“…Recent studies using mammalian inner ear cell cultures suggest manipulating the Notch and Wnt pathways are critical to regrowing damaged hair cells. 46 , 47 Interestingly, while there are conflicting results for upregulation and downregulation of Notch signaling as a mechanism to promote regeneration, upregulation of Wnt signaling is consistently necessary. 46 , 47 Krm1 is expressed in the support cells of the mammalian cochlea, making it a potential target for therapeutic intervention: inhibition of Krm1 function might be required for support cells to re-enter a more progenitor-like stage to then differentiate as mechanosensory hair cells to restore hearing.…”

“… 46 , 47 Interestingly, while there are conflicting results for upregulation and downregulation of Notch signaling as a mechanism to promote regeneration, upregulation of Wnt signaling is consistently necessary. 46 , 47 Krm1 is expressed in the support cells of the mammalian cochlea, making it a potential target for therapeutic intervention: inhibition of Krm1 function might be required for support cells to re-enter a more progenitor-like stage to then differentiate as mechanosensory hair cells to restore hearing. Future work will be needed to determine if regulation of Krm1 function also plays a role in hair regeneration in the inner ear.…”

Molecular insights into the atypical activation mechanism of GPR156 in maintaining auditory function

“…AAV.7m8 was used as the AAV capsid because it can efficiently infect HCs ( 36, 37 ), and this along with the targeted plasmid and helper plasmid were delivered to HEK-293T cells at molar ratio 1:1:1 by linear polyethylenimine (Yeasen, 40816ES02). AAV purification and titer assays were performed according to the previously published protocol ( 38, 39 ). The GPR156-shRNA1 sequence was cgg agc atg caa tgt agc ttt.…”

Hair Cell Regeneration: From Animals to Humans

“…In addition, Sox2 haploinsufficiency promotes hair cell regeneration and mitosis induced by the Wnt/β-catenin signaling pathway after damage in the neonatal cochlea in vivo [ 136 ]. Recently, Zhang et al [ 137 ] showed that adeno-associated virus-neuroepithelia transforming gene 1 ( Net1 ) can also activate the Wnt/β-catenin signaling pathway, promoting supporting cell proliferation and hair cell regeneration in neonatal cochleae in vivo . Net1 is a guanine nucleotide exchange factor that regulates RhoA activity and is implicated in cell proliferation, apoptosis, and differentiation [ 138 , 139 ].…”