Reprogramming by drug-like molecules leads to regeneration of cochlear hair cell-like cells in adult mice.

Strategies to overcome irreversible cochlear hair cell (HC) damage and loss in mammals are of vital importance to hearing recovery in patients with permanent hearing loss. In mature mammalian cochlea, co-activation of Myc and Notch1 reprograms supporting cells (SC) and promotes HC regeneration. Understanding of the underlying mechanisms may aid the development of a clinically relevant approach to achieve HC regeneration in the nontransgenic mature cochlea. By single-cell RNAseq, we show that MYC/NICD "rejuvenates" the adult mouse cochlea by activating multiple pathways including Wnt and cyclase activator of cyclic AMP (cAMP), whose blockade suppresses HC-like cell regeneration despite Myc/Notch activation. We screened and identified a combination (the cocktail) of drug-like molecules composing of small molecules and small interfering RNAs to activate the pathways of Myc, Notch1, Wnt and cAMP. We show that the cocktail effectively replaces Myc and Notch1 transgenes and reprograms fully mature wild-type (WT) SCs for HC-like cells regeneration in vitro. Finally, we demonstrate the cocktail is capable of reprogramming adult cochlea for HC-like cells regeneration in WT mice with HC loss in vivo. Our study identifies a strategy by a clinically relevant approach to reprogram mature inner ear for HC-like cells regeneration, laying the foundation for hearing restoration by HC regeneration.

Non-flammable solvent-free liquid polymer electrolyte for lithium metal batteries.

As a replacement for highly flammable and volatile organic liquid electrolyte, solid polymer electrolyte shows attractive practical prospect in high-energy lithium metal batteries. However, unsatisfied interface performance and ionic conductivities are two critical challenges. A common strategy involves introducing organic solvents or plasticizers, but this violates the original intention of security design. Here, an electrolyte concept called liquid polymer electrolyte without any small molecular solvents is proposed for safe and high-performance batteries, based on the design of a room-temperature liquid-state brush-like polymer as the sole solvent of lithium salts. This liquid polymer electrolyte is non-flammable and exhibits high ionic conductivity (1.09 [Formula: see text] 10-4 S cm-1 at 25 °C), significant lithium dendrite suppression, and stable long-term cycling over a wide operating temperature range ( ≥ 1000 cycles at 60 °C and 90 °C). Moreover, the pouch cell can resist thermal abuse, vacuum environment, and mechanical abuse. This electrolyte and design strategy are expected to provide enlightening ideas for the development of safe and high-performance polymer electrolytes.

Renewed proliferation in adult mouse cochlea and regeneration of hair cells.

The adult mammalian inner ear lacks the capacity to divide or regenerate. Damage to inner ear generally leads to permanent hearing loss in humans. Here, we present that reprogramming of the adult inner ear induces renewed proliferation and regeneration of inner ear cell types. Co-activation of cell cycle activator Myc and inner ear progenitor gene Notch1 induces robust proliferation of diverse adult cochlear sensory epithelial cell types. Transient MYC and NOTCH activities enable adult supporting cells to respond to transcription factor Atoh1 and efficiently transdifferentiate into hair cell-like cells. Furthermore, we uncover that mTOR pathway participates in MYC/NOTCH-mediated proliferation and regeneration. These regenerated hair cell-like cells take up the styryl dye FM1-43 and are likely to form connections with adult spiral ganglion neurons, supporting that Myc and Notch1 co-activation is sufficient to reprogram fully mature supporting cells to proliferate and regenerate hair cell-like cells in adult mammalian auditory organs.