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Small extracellular vesicles (sEVs) act as a critical mediator in intercellular communication. Compared to sEVs derived from in vitro sources, tissue-derived sEVs can reflect the in vivo signals released from specific tissues more accurately. Currently, studies on the role of sEVs in the cochlea have relied on studying sEVs from in vitro sources. This study evaluates three cochlear tissue digestion and cochlear tissue-derived sEV (CDsEV) isolation methods, and first proposes that the optimal approach for isolating CDsEVs using collagenase D and DNase І combined with sucrose density gradient centrifugation. Furthermore, it comprehensively investigates CDsEV contents and cell origins. Small RNA sequencing and proteomics are performed to analyze the miRNAs and proteins of CDsEVs. The miRNAs and proteins of CDsEVs are crucial for maintaining normal auditory function. Among them, FGFR1 in CDsEVs may mediate the survival of cochlear hair cells via sEVs. Finally, the joint analysis of single CDsEV sequencing and single-cell RNA sequencing data is utilized to trace cellular origins of CDsEVs. The results show that different types of cochlear cells secrete different amounts of CDsEVs, with Kölliker's organ cells and supporting cells secrete the most. The findings are expected to enhance the understanding of CDsEVs in the cochlea., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

G protein-coupled receptors (GPCRs) mediate most cellular responses to hormones, neurotransmitters, and environmental stimulants. However, whether GPCRs participate in tissue homeostasis through ferroptosis remains unclear. Here we identify that GPR56/ADGRG1 renders cells resistant to ferroptosis and deficiency of GPR56 exacerbates ferroptosis-mediated liver injury induced by doxorubicin (DOX) or ischemia-reperfusion (IR). Mechanistically, GPR56 decreases the abundance of phospholipids containing free polyunsaturated fatty acids (PUFAs) by promoting endocytosis-lysosomal degradation of CD36. By screening a panel of steroid hormones, we identified that 17α-hydroxypregnenolone (17-OH PREG) acts as an agonist of GPR56 to antagonize ferroptosis and efficiently attenuates liver injury before or after insult. Moreover, disease-associated GPR56 mutants were unresponsive to 17-OH PREG activation and insufficient to defend against ferroptosis. Together, our findings uncover that 17-OH PREG-GPR56 axis-mediated signal transduction works as a new anti-ferroptotic pathway to maintain liver homeostasis, providing novel insights into the potential therapy for liver injury., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The proliferative and migratory abilities of vascular smooth muscle cells (VSMCs) play a crucial role in neointima formation following vascular injury. Skp2 facilitates proliferation and migration in cells through cell cycle regulation, presenting an important therapeutic target for atherosclerosis, pulmonary hypertension, and vascular restenosis. This study aimed to identify a natural product capable of inhibiting neointima formation post vascular injury. Here, we demonstrate that troxerutin, a flavonoid, significantly reduced viability and downregulated Skp2 in VSMCs. Moreover, troxerutin exhibited anti-proliferative effects on VSMCs and mitigated neointima formation. These findings collectively elucidate the intrinsic mechanism of troxerutin in treating atherosclerosis, pulmonary hypertension, and vascular restenosis by targeting the E3-linked enzyme Skp2., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Mammalian hair cells (HCs) are arranged spirally along the cochlear axis and correspond to different frequency ranges. Serving as primary sound detectors, HCs spatially segregate component frequencies into a topographical map. HCs display significant diversity in anatomical and physiological characteristics, yet little is known about the organization of the cochleotopic map of HCs or the molecules involved in this process. Using single-cell RNA sequencing, we determined the distinct molecular profiles of inner hair cells and outer hair cells, and we identified numerous position-dependent genes that were expressed as gradients. Newly identified genes such as Ptn, Rxra, and Nfe2l2 were found to be associated with tonotopy. We employed the SCENIC algorithm to predict the transcription factors that potentially shape these tonotopic gradients. Furthermore, we confirmed that Nfe2l2, a tonotopy-related transcription factor, is critical in mice for sensing low-to-medium sound frequencies in vivo. the analysis of cell-cell communication revealed potential receptor-ligand networks linking inner hair cells to spiral ganglion neurons, including pathways such as BDNF-Ntrk and PTN-Scd4, which likely play essential roles in tonotopic maintenance. Overall, these findings suggest that molecular gradients serve as the organizing principle for maintaining the selection of sound frequencies by HCs., (© 2024. Science China Press.)

Many clustered regularly interspaced short palindromic repeat and CRISPR-associated protein 12b (CRISPR-Cas12b) nucleases have been computationally identified, yet their potential for genome editing remains largely unexplored. In this study, we conducted a GFP-activation assay screening 13 Cas12b nucleases for mammalian genome editing, identifying five active candidates. Candidatus hydrogenedentes Cas12b (ChCas12b) was found to recognize a straightforward WTN (W = T or A) proto-spacer adjacent motif (PAM), thereby dramatically expanding the targeting scope. Upon optimization of the single guide RNA (sgRNA) scaffold, ChCas12b exhibited activity comparable to SpCas9 across a panel of nine endogenous loci. Additionally, we identified nine mutations enhancing ChCas12b specificity. More importantly, we demonstrated that both ChCas12b and its high-fidelity variant, ChCas12b-D496A, enabled allele-specific disruption of genes harboring single nucleotide polymorphisms (SNPs). These data position ChCas12b and its high-fidelity counterparts as promising tools for both fundamental research and therapeutic applications., (Copyright © 2024 Science China Press. Published by Elsevier B.V. All rights reserved.)

Fibroblast growth factor receptor 1 (FGFR1) is emerging as a promising molecular target of lung cancer, and various FGFR1 inhibitors have exhibited significant therapeutic effects on lung cancer in preclinical research. Due to their low targeting ability or bioavailability, direct administration of these inhibitors may cause side effects. Herein, a hydrogelator, Nap-Phe-Phe-Phe-Glu-Thr-Glu-Leu-Tyr-OH ( Nap-Y ), was rationally designed to coassemble with an FGFR1 inhibitor nintedanib ( Nin ) to form a peptide hydrogel Gel Y/Nin for localized administration and FGFR1-triggered release of Nin . Upon specific phosphorylation by FGFR1 overexpressed on lung cancer cells, Nap-Y in Gel Y/Nin is converted to the hydrophilic product Nap-Phe-Phe-Phe-Glu-Thr-Glu-Leu-Tyr(H 2 PO 3 )-OH ( Nap-Yp ), leading to dehydrogelation of the gel and subsequent Nin release. In vitro experiments demonstrate that the release of Nin in a sustained manner from Gel Y/Nin significantly suppresses the survival, migration, and invasion of A549 cells by inhibiting FGFR1 expression and its phosphorylation function on downstream signaling molecules. Nude mouse studies show that Gel Y/Nin exhibits enhanced therapeutic efficacy on lung tumor than free Nin . We anticipate that Gel Y/Nin will be utilized for lung cancer treatment in clinical settings in the near future.

Ototoxicity and nephrotoxicity are the most prevalent side effects of aminoglycoside antibiotics (gentamicin, amikacin, neomycin) and platinum anti-tumor drugs (cisplatin, carboplatin). The inner ear and kidney share similarities in drug deposition and toxicity, but the underlying pathophysiological mechanisms remain unclear. Investigating the shared mechanisms and metabolic alterations in these distinct organs will provide valuable insights for clinical therapy. A strong correlation has been identified between the spatiotemporal accumulation patterns of neomycin and the specific occurrence of lipid metabolism disorders in these two organs. The primary allocation of neomycin to mitochondria results in a notable escalation in the accumulation of lipid droplets (LDs) and more interactions between mitochondria and LDs, leading to a sequence of disturbances in lipid metabolism, such as increased lipid ROS and the blocked transfer of fatty acids from LDs to mitochondria. PGC-1 α deficiency worsens the neomycin-induced disorders in lipid metabolism and intensifies the pathological interactions between mitochondria and LDs, as indicated by the exacerbated disturbance of dynamic LD turnover, increased level of oxidized lipids and decreased use of fatty acids. This investigation provides a fresh perspective on the lipid metabolic dysfunction related to mitochondria-LD interactions in drug-induced ototoxicity and nephrotoxicity, potentially providing novel avenues for intervention strategies., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Authors.)

Mammalian cochlea spiral ganglion neurons (SGNs) are crucial for sound transmission, they can be damaged by chemotherapy drug cisplatin and lead to irreversible sensorineural hearing loss (SNHL), while such damage can also render cochlear implants ineffective. However, the mechanisms underlying cisplatin-induced SGNs damage and subsequent SNHL are still under debate and there is no currently effective clinical treatment. Here, this study demonstrates that ferroptosis is triggered in SGNs following exposure to cisplatin. Inhibiting ferroptosis protects against cisplatin-induced SGNs damage and hearing loss, while inducing ferroptosis intensifies these effects. Furthermore, cisplatin prompts nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy in SGNs, while knocking down NCOA4 mitigates cisplatin-induced ferroptosis and hearing loss. Notably, the upstream regulator of NCOA4 is identified and transcription factor forkhead box O1 (FOXO1) is shown to directly suppress NCOA4 expression in SGNs. The knocking down of FOXO1 amplifies NCOA4-mediated ferritinophagy, increases ferroptosis and lipid peroxidation, while disrupting the interaction between FOXO1 and NCOA4 in NCOA4 knock out mice prevents the cisplatin-induced SGN ferroptosis and hearing loss. Collectively, this study highlights the critical role of the FOXO1-NCOA4 axis in regulating ferritinophagy and ferroptosis in cisplatin-induced SGNs damage, offering promising therapeutic targets for SNHL mitigation., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Photonic crystals are a new class of optical microstructure materials characterized by a dielectric constant that varies periodically with space and features a photonic bandgap. Inspired by natural photonic crystals such as butterfly scales, a series of artificial photonic crystals are developed for use in integrated photonic platforms, biosensing, communication, and other fields. Among them, colloidal photonic crystals (CPCs) have gained widespread attention due to their excellent optical properties and advantages, such as ease of preparation and functionalization. This work reviews the classification and self-assembly principles of CPCs, details some of the latest biomedical applications of large-area, high-quality CPCs prepared using advanced self-assembly methods, summarizes the existing challenges in CPC construction and application, and anticipates future development directions and optimization strategy. With further advancements, CPCs are expected to play a more critical role in biosensors, drug delivery, cell research, and other fields, bringing significant benefits to biomedical research and clinical practice., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Mammalian cochlear hair cells (HCs) are essential for hearing, and damage to HCs results in severe hearing impairment. Damaged HCs can be regenerated by neighboring supporting cells (SCs), thus the functional regeneration of HCs is the main goal for the restoration of auditory function in vivo. Here, cochlear SC trans-differentiation into outer and inner HC by the induced expression of the key transcription factors Atoh1 and its co-regulators Gfi1, Pou4f3, and Six1 (GPAS), which are necessary for SCs that are destined for HC development and maturation via the AAV-ie targeting the inner ear stem cells are successfully achieved. Single-cell nuclear sequencing and lineaging tracing results showed that the majority of new Atoh1-derived HCs are in a state of initiating differentiation, while GP (Gfi1, Pou4f3) and GPS (Gfi1, Pou4f3, and Six1) enhanced the Atoh1-induced new HCs into inner and outer HCs. Moreover, the patch-clamp analysis indicated that newborn inner HCs induced by GPAS forced expression have similar electrophysiological characteristics to those of native inner HCs. Also, GPAS can induce HC regeneration in the HC-damaged mice model. In summary, the study demonstrates that AAV-mediated co-regulation of multiple genes, such as GPAS, is an effective means to achieve functional HC regeneration in the mouse cochlea., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Hair cell (HC) damage is a leading cause of sensorineural hearing loss, and in mammals supporting cells (SCs) are unable to divide and regenerate HCs after birth spontaneously. Procollagen C-endopeptidase enhancer 2 (Pcolce2), which encodes a glycoprotein that acts as a functional procollagen C protease enhancer, was screened as a candidate regulator of SC plasticity in our previous study. In the current study, we used adeno-associated virus (AAV)-ie (a newly developed adeno-associated virus that targets SCs) to overexpress Pcolce2 in SCs. AAV-Pcolce2 facilitated SC re-entry into the cell cycle both in cultured cochlear organoids and in the postnatal cochlea. In the neomycin-damaged model, regenerated HCs were detected after overexpression of Pcolce2, and these were derived from SCs that had re-entered the cell cycle. These findings reveal that Pcolce2 may serve as a therapeutic target for the regeneration of HCs to treat hearing loss., (© 2024 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

Advanced artificial nerve conduits offer a promising alternative for nerve injury repair. Current research focuses on improving the therapeutic effectiveness of nerve conduits by optimizing scaffold materials and functional components. In this study, a novel poly(3,4-ethylenedioxythiophene) (PEDOT)-integrated fish swim bladder (FSB) is presented as a conductive nerve conduit with ordered topology and electrical stimulation to promote nerve regeneration. PEDOT nanomaterials and adhesive peptides (IKVAV) are successfully incorporated onto the decellularized FSB substrate through pre-coating with polydopamine. The obtained PEDOT/IKVAV-integrated FSB substrate exhibits outstanding mechanical properties, high electrical conductivity, stability, as well as excellent biocompatibility and bioadhesive properties. In vitro studies confirm that the PEDOT/IKVAV-integrated FSB can effectively facilitate the growth and directional extension of pheochromocytoma 12 cells and dorsal root ganglion neurites. In addition, in vivo experiments demonstrate that the proposed PEDOT/IKVAV-integrated FSB conduit can accelerate defective nerve repair and functional restoration. The findings indicate that the FSB-derived conductive nerve conduits with multiple regenerative inducing signals integration provide a conducive milieu for nerve regeneration, exhibiting great potential for repairing long-segment neural defects., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

The physiological interactions between the peripheral and central auditory systems are crucial for auditory information transmission and perception, while reliable models for auditory neural circuits are currently lacking. To address this issue, mouse and human neural pathways are generated by utilizing a carbon nanotube nanofiber system. The super-aligned pattern of the scaffold renders the axons of the bipolar and multipolar neurons extending in a parallel direction. In addition, the electrical conductivity of the scaffold maintains the electrophysiological activity of the primary mouse auditory neurons. The mouse and human primary neurons from peripheral and central auditory units in the system are then co-cultured and showed that the two kinds of neurons form synaptic connections. Moreover, neural progenitor cells of the cochlea and auditory cortex are derived from human embryos to generate region-specific organoids and these organoids are assembled in the nanofiber-combined 3D system. Using optogenetic stimulation, calcium imaging, and electrophysiological recording, it is revealed that functional synaptic connections are formed between peripheral neurons and central neurons, as evidenced by calcium spiking and postsynaptic currents. The auditory circuit model will enable the study of the auditory neural pathway and advance the search for treatment strategies for disorders of neuronal connectivity in sensorineural hearing loss., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Cochlear implants can directly activate the auditory system's primary sensory neurons, the spiral ganglion neurons (SGNs), via circumvention of defective cochlear hair cells. This bypass restores auditory input to the brainstem. SGN loss etiologies are complex, with limited mammalian regeneration. Protecting and revitalizing SGN is critical. Tissue engineering offers a novel therapeutic strategy, utilizing seed cells, biomolecules, and scaffold materials to create a cellular environment and regulate molecular cues. This review encapsulates the spectrum of both human and animal research, collating the factors contributing to SGN loss, the latest advancements in the utilization of exogenous stem cells for auditory nerve repair and preservation, the taxonomy and mechanism of action of standard biomolecules, and the architectural components of scaffold materials tailored for the inner ear. Furthermore, we delineate the potential and benefits of the biohybrid neural interface, an incipient technology in the realm of implantable devices. Nonetheless, tissue engineering requires refined cell selection and differentiation protocols for consistent SGN quality. In addition, strategies to improve stem cell survival, scaffold biocompatibility, and molecular cue timing are essential for biohybrid neural interface integration., (© 2024. The Author(s).)

Nerve guidance conduits (NGCs) are considered as promising treatment strategy and frontier trend for peripheral nerve regeneration, while their therapeutic outcomes are limited by the lack of controllable drug delivery and available physicochemical cues. Herein, novel aligned piezoelectric nanofibers derived hydrogel NGCs with ultrasound (US)-triggered electrical stimulation (ES) and controllable drug release for repairing peripheral nerve injury are proposed. The inner layer of the NGCs is the barium titanate piezoelectric nanoparticles (BTNPs)-doped polyvinylidene fluoride-trifluoroethylene [BTNPs/P(VDF-TrFE)] electrospinning nanofibers with improved piezoelectricity and aligned orientation. The outer side of the NGCs is the thermoresponsive poly(N-isopropylacrylamide) hybrid hydrogel with bioactive drug encapsulation. Such NGCs can not only induce neuronal-oriented extension and promote neurite outgrowth with US-triggered wireless ES, but also realize the controllable nerve growth factor release with the hydrogel shrinkage under US-triggered heating. Thus, the NGC can positively accelerate the functional recovery and nerve axonal regeneration of rat models with long sciatic nerve defects. It is believed that the proposed US-responsive aligned piezoelectric nanofibers derived hydrogel NGCs will find important applications in clinic neural tissue engineering., (© 2024 Wiley‐VCH GmbH.)

Irreversible damage to hair cells (HCs) in the cochlea leads to hearing loss. Cochlear supporting cells (SCs) in the murine cochlea have the potential to differentiate into HCs. Neuron membrane glycoprotein M6B (Gpm6b) as a four-transmembrane protein is a potential regulator of HC regeneration according to our previous research. In this study, we found that AAV-ie-mediated Gpm6b overexpression promoted SC-derived organoid expansion. Enhanced Gpm6b prevented the normal decrease in SC plasticity as the cochlea develops by supporting cells re-entry cell cycle and facilitating the SC-to-HC transformation. Also, overexpression of Gpm6b in the organ of Corti through the round window membrane injection facilitated the trans-differentiation of Lgr5 + SCs into HCs. In conclusion, our results suggest that Gpm6b overexpression promotes HC regeneration and highlights a promising target for hearing repair using the inner ear stem cells combined with AAV., (© 2024 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

Hearing loss and deafness, as a worldwide disability disease, have been troubling human beings. However, the auditory organ of the inner ear is highly heterogeneous and has a very limited number of cells, which are largely uncharacterized in depth. Recently, with the development and utilization of single-cell RNA sequencing (scRNA-seq), researchers have been able to unveil the complex and sophisticated biological mechanisms of various types of cells in the auditory organ at the single-cell level and address the challenges of cellular heterogeneity that are not resolved through by conventional bulk RNA sequencing (bulk RNA-seq). Herein, we reviewed the application of scRNA-seq technology in auditory research, with the aim of providing a reference for the development of auditory organs, the pathogenesis of hearing loss, and regenerative therapy. Prospects about spatial transcriptomic scRNA-seq, single-cell based genome, and Live-seq technology will also be discussed., (© 2023. Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences.)

Organ-on-chips can highly simulate the complex physiological functions of organs, exhibiting broad application prospects in developmental research, disease simulation, as well as new drug research and development. However, there is still less concern about effectively constructing cochlea-on-chips. Here, a novel cochlear organoids-integrated conductive hydrogel biohybrid system with cochlear implant electroacoustic stimulation (EAS) for cochlea-on-a-chip construction and high-throughput drug screening, is presented. Benefiting from the superior biocompatibility and electrical property of conductive hydrogel, together with cochlear implant EAS, the inner ear progenitor cells can proliferate and spontaneously shape into spheres, finally forming cochlear organoids with good cell viability and structurally mature hair cells. By incorporating these progenitor cells-encapsulated hydrogels into a microfluidic-based cochlea-on-a-chip with culture chambers and a concentration gradient generator, a dynamic and high-throughput evaluation of inner ear disease-related drugs is demonstrated. These results indicate that the proposed cochlea-on-a-chip platform has great application potential in organoid cultivation and deafness drug evaluation., (© 2024 The Authors. Advanced Materials published by Wiley‐VCH GmbH.)

Background: Autosomal recessive deafness 9, caused by mutations of the OTOF gene, is characterised by congenital or prelingual, severe-to-complete, bilateral hearing loss. However, no pharmacological treatment is currently available for congenital deafness. In this Article, we report the safety and efficacy of gene therapy with an adeno-associated virus (AAV) serotype 1 carrying a human OTOF transgene (AAV1-hOTOF) as a treatment for children with autosomal recessive deafness 9., Methods: This single-arm, single-centre trial enrolled children (aged 1-18 years) with severe-to-complete hearing loss and confirmed mutations in both alleles of OTOF, and without bilateral cochlear implants. A single injection of AAV1-hOTOF was administered into the cochlea through the round window. The primary endpoint was dose-limiting toxicity at 6 weeks after injection. Auditory function and speech were assessed by appropriate auditory perception evaluation tools. All analyses were done according to the intention-to-treat principle. This trial is registered with Chinese Clinical Trial Registry, ChiCTR2200063181, and is ongoing., Findings: Between Oct 19, 2022, and June 9, 2023, we screened 425 participants for eligibility and enrolled six children for AAV1-hOTOF gene therapy (one received a dose of 9 × 10 11 vector genomes [vg] and five received 1·5 × 10 12 vg). All participants completed follow-up visits up to week 26. No dose-limiting toxicity or serious adverse events occurred. In total, 48 adverse events were observed; 46 (96%) were grade 1-2 and two (4%) were grade 3 (decreased neutrophil count in one participant). Five children had hearing recovery, shown by a 40-57 dB reduction in the average auditory brainstem response (ABR) thresholds at 0·5-4·0 kHz. In the participant who received the 9 × 10 11 vg dose, the average ABR threshold was improved from greater than 95 dB at baseline to 68 dB at 4 weeks, 53 dB at 13 weeks, and 45 dB at 26 weeks. In those who received 1·5 × 10 12 AAV1-hOTOF, the average ABR thresholds changed from greater than 95 dB at baseline to 48 dB, 38 dB, 40 dB, and 55 dB in four children with hearing recovery at 26 weeks. Speech perception was improved in participants who had hearing recovery., Interpretation: AAV1-hOTOF gene therapy is safe and efficacious as a novel treatment for children with autosomal recessive deafness 9., Funding: National Natural Science Foundation of China, National Key R&D Program of China, Science and Technology Commission of Shanghai Municipality, and Shanghai Refreshgene Therapeutics., Competing Interests: Declaration of interests KG is a staff member at the Shanghai Refreshgene Therapeutics. ZC is a cofounder of Salubritas Therapeutics. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Cisplatin-induced hearing loss is a common side effect of cancer chemotherapy in clinics; however, the mechanism of cisplatin-induced ototoxicity is still not completely clarified. Cisplatin-induced ototoxicity is mainly associated with the production of reactive oxygen species, activation of apoptosis, and accumulation of intracellular lipid peroxidation, which also is involved in ferroptosis induction. In this study, the expression of TfR1, a ferroptosis biomarker, was upregulated in the outer hair cells of cisplatin-treated mice. Moreover, several key ferroptosis regulator genes were altered in cisplatin-damaged cochlear explants based on RNA sequencing, implying the induction of ferroptosis. Ferroptosis-related Gpx4 and Fsp1 knockout mice were established to investigate the specific mechanisms associated with ferroptosis in cochleae. Severe outer hair cell loss and progressive damage of synapses in inner hair cells were observed in Atoh1-Gpx4 -/- mice. However, Fsp1 -/- mice showed no significant hearing phenotype, demonstrating that Gpx4, but not Fsp1, may play an important role in the functional maintenance of HCs. Moreover, findings showed that FDA-approved luteolin could specifically inhibit ferroptosis and alleviate cisplatin-induced ototoxicity through decreased expression of transferrin and intracellular concentration of ferrous ions. This study indicated that ferroptosis inhibition through the reduction of intracellular ferrous ions might be a potential strategy to prevent cisplatin-induced hearing loss., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Noise-induced hearing loss (NIHL) is a highly prevalent form of sensorineural hearing damage that has significant negative effects on individuals of all ages and there are no effective drugs approved by the US Food and Drug Administration. In this study, we unveil the potential of superparamagnetic iron oxide nanoparticle assembly (SPIOCA) to reshape the dysbiosis of gut microbiota for treating NIHL. This modulation inhibits intestinal inflammation and oxidative stress responses, protecting the integrity of the intestinal barrier. Consequently, it reduces the transportation of pathogens and inflammatory factors from the bloodstream to the cochlea. Additionally, gut microbiota-modulated SPIOCA-induced metabolic reprogramming in the gut-inner ear axis mainly depends on the regulation of the sphingolipid metabolic pathway, which further contributes to the restoration of hearing function. Our study confirms the role of the microbiota-gut-inner ear axis in NIHL and provides a novel alternative for the treatment of NIHL and other microbiota dysbiosis-related diseases., (© The Author(s) 2024. Published by Oxford University Press on behalf of China Science Publishing & Media Ltd.)

Mutations in OTOFERLIN (OTOF) lead to the autosomal recessive deafness 9 (DFNB9). The efficacy of adeno-associated virus (AAV)-mediated OTOF gene replacement therapy is extensively validated in Otof-deficient mice. However, the clinical safety and efficacy of AAV-OTOF is not reported. Here, AAV-OTOF is generated using good manufacturing practice and validated its efficacy and safety in mouse and non-human primates in order to determine the optimal injection dose, volume, and administration route for clinical trials. Subsequently, AAV-OTOF is delivered into one cochlea of a 5-year-old deaf patient and into the bilateral cochleae of an 8-year-old deaf patient with OTOF mutations. Obvious hearing improvement is detected by the auditory brainstem response (ABR) and the pure-tone audiometry (PTA) in these two patients. Hearing in the injected ear of the 5-year-old patient can be restored to the normal range at 1 month after AAV-OTOF injection, while the 8-year-old patient can hear the conversational sounds. Most importantly, the 5-year-old patient can hear and recognize speech only through the AAV-OTOF-injected ear. This study is the first to demonstrate the safety and efficacy of AAV-OTOF in patients, expands and optimizes current OTOF-related gene therapy and provides valuable information for further application of gene therapies for deafness., (© 2024 The Authors. Advanced Science published by Wiley-VCH GmbH.)

According to the World Health Organization's world report on hearing, nearly 2.5 billion people worldwide will suffer from hearing loss by 2050, which may contribute to a severe impact on individual life quality and national economies. Sensorineural hearing loss (SNHL) occurs commonly as a result of noise exposure, aging, and ototoxic drugs, and is pathologically characterized by the impairment of mechanosensory hair cells of the inner ear, which is mainly triggered by reactive oxygen species accumulation, inflammation, and mitochondrial dysfunction. Though recent advances have been made in understanding the ability of cochlear repair and regeneration, there are still no effective therapeutic drugs for SNHL. Chinese herbal medicine which is widely distributed and easily accessible in China has demonstrated a unique curative effect against SNHL with higher safety and lower cost compared with Western medicine. Herein we present trends in research for Chinese herbal medicine for the treatment of SNHL, and elucidate their molecular mechanisms of action, to pave the way for further research and development of novel effective drugs in this field., (© 2024 The Authors.)

Transition metal carbides and nitrides (MXenes) are crystal nanomaterials with a number of surface functional groups such as fluorine, hydroxyl, and oxygen, which can be used as carriers for proteins and drugs. MXenes have excellent biocompatibility, electrical conductivity, surface hydrophilicity, mechanical properties and easy surface modification. However, at present, the stability of most MXenes needs to be improved, and more synthesis methods need to be explored. MXenes are good substrates for nerve cell regeneration and nerve reconstruction, which have broad application prospects in the repair of nervous system injury. Regarding the application of MXenes in neuroscience, mainly at the cellular level, the long-term in vivo biosafety and effects also need to be further explored. This review focuses on the progress of using MXenes in nerve regeneration over the last few years; discussing preparation of MXenes and their biocompatibility with different cells as well as the regulation by MXenes of nerve cell regeneration in two-dimensional and three-dimensional environments in vitro. MXenes have great potential in regulating the proliferation, differentiation, and maturation of nerve cells and in promoting regeneration and recovery after nerve injury. In addition, this review also presents the main challenges during optimization processes, such as the preparation of stable MXenes and long-term in vivo biosafety, and further discusses future directions in neural tissue engineering., Competing Interests: None

More than 6% of the world's population is suffering from hearing loss and balance disorders. The inner ear is the organ that senses sound and balance. Although inner ear disorders are common, there are limited ways to intervene and restore its sensory and balance functions. The development and establishment of biologically therapeutic interventions for auditory disorders require clarification of the basics of signaling pathways that control inner ear development and the establishment of endogenous or exogenous cell-based therapeutic methods. In vitro models of the inner ear, such as organoid systems, can help identify new protective or regenerative drugs, develop new gene therapies, and be considered as potential tools for future clinical applications. Advances in stem cell technology and organoid culture offer unique opportunities for modeling inner ear diseases and developing personalized therapies for hearing loss. Here, we review and discuss the mechanisms for the establishment and the potential applications of inner ear organoids., Competing Interests: The authors declare that there are no conflicts of interest., (© 2024 The Authors. Smart Medicine published by Wiley‐VCH GmbH on behalf of Wenzhou Institute, University of Chinese Academy of Sciences.)

Inner ear hair cells detect sound vibration through the deflection of mechanosensory stereocilia. Cytoplasmic protein TPRN has been shown to localize at the taper region of the stereocilia, and mutations in TPRN cause hereditary hearing loss through an unknown mechanism. Here, using biochemistry and dual stimulated emission depletion microscopy imaging, we show that the TPRN, together with its binding proteins CLIC5 and PTPRQ, forms concentric rings in the taper region of stereocilia. The disruption of TPRN rings, triggered by the competitive inhibition of the interaction of TPRN and CLIC5 or exogenous TPRN overexpression, leads to stereocilia degeneration and severe hearing loss. Most importantly, restoration of the TPRN rings can rescue the damaged auditory function of Tprn knockout mice by exogenously expressing TPRN at an appropriate level in HCs via promoter recombinant adeno-associated virus (AAV). In summary, our results reveal highly structured TPRN rings near the taper region of stereocilia that are crucial for stereocilia function and hearing. Also, TPRN ring restoration in stereocilia by AAV-Tprn effectively repairs damaged hearing, which lays the foundation for the clinical application of AAV-mediated gene therapy in patients with TPRN mutation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Hearing loss has become increasingly prevalent and causes considerable disability, thus gravely burdening the global economy. Irreversible loss of hair cells is a main cause of sensorineural hearing loss, and currently, the only relatively effective clinical treatments are limited to digital hearing equipment like cochlear implants and hearing aids, but these are of limited benefit in patients. It is therefore urgent to understand the mechanisms of damage repair in order to develop new neuroprotective strategies. At present, how to promote the regeneration of functional hair cells is a key scientific question in the field of hearing research. Multiple signaling pathways and transcriptional factors trigger the activation of hair cell progenitors and ensure the maturation of newborn hair cells, and in this article, we first review the principal mechanisms underlying hair cell reproduction. We then further discuss therapeutic strategies involving the co-regulation of multiple signaling pathways in order to induce effective functional hair cell regeneration after degeneration, and we summarize current achievements in hair cell regeneration. Lastly, we discuss potential future approaches, such as small molecule drugs and gene therapy, which might be applied for regenerating functional hair cells in the clinic., (© 2023. The Author(s).)

The gut microbiota play a pivotal role in human health. Emerging evidence indicates that gut microbes participate in the progression of tumorigenesis through the generation of carcinogenic metabolites. However, the underlying molecular mechanism is largely unknown. In the present study we show that a tryptophan metabolite derived from Peptostreptococcus anaerobius, trans-3-indoleacrylic acid (IDA), facilitates colorectal carcinogenesis. Mechanistically, IDA acts as an endogenous ligand of an aryl hydrocarbon receptor (AHR) to transcriptionally upregulate the expression of ALDH1A3 (aldehyde dehydrogenase 1 family member A3), which utilizes retinal as a substrate to generate NADH, essential for ferroptosis-suppressor protein 1(FSP1)-mediated synthesis of reduced coenzyme Q10. Loss of AHR or ALDH1A3 largely abrogates IDA-promoted tumour development both in vitro and in vivo. It is interesting that P. anaerobius is significantly enriched in patients with colorectal cancer (CRC). IDA treatment or implantation of P. anaerobius promotes CRC progression in both xenograft model and Apc Min/+ mice. Together, our findings demonstrate that targeting the IDA-AHR-ALDH1A3 axis should be promising for ferroptosis-related CRC treatment., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

OTOF mutations are the principal causes of auditory neuropathy. There are reports on Otof-related gene therapy in mice, but there is no preclinical research on the drug evaluations. Here, Anc80L65 and the mouse hair cell-specific Myo15 promoter (mMyo15) are used to selectively and effectively deliver human OTOF to hair cells in mice and nonhuman primates to evaluate the efficacy and safety of OTOF gene therapy drugs. A new dual-AAV-OTOF-hybrid strategy to transfer full-length OTOF is generated, which can stably restore hearing in adult OTOF p.Q939*/Q939* mice with profound deafness, with the longest duration being at least 150 days, and the best therapeutic effect without difference in hearing from wild-type mice. An AAV microinjection method into the cochlea of cynomolgus monkeys without hearing impairment is further established and found the OTOF can be safely and effectively driven by the mMyo15 promoter in hair cells. In addition, the therapeutic dose of AAV drugs has no impact on normal hearing and does not cause significant systemic toxicity both in mouse and nonhuman primates. In summary, this study develops a potential gene therapy strategy for DFNB9 patients in the clinic and provides complete, standardized, and systematic research data for clinical research and application., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Noise-induced hearing loss (NIHL) is a common outcome of excessive reactive oxygen species in the cochlea, and the targeted delivery of antioxidants to the inner ear is a potential therapeutic strategy. In this paper, a novel natural biomaterials-derived multifunctional delivery system using silk fibroin-polydopamine (PDA)-composited inverse opal microcarriers (PDA@SFMCs) is presented for inner ear drug delivery and NIHL therapy. Due to their large specific surface area and interpenetrating nanochannels, PDA@SFMCs can rapidly load active biomolecules making them a convenient medium for the storage and delivery of such molecules. In addition, surface modification of PDA enables the microcarriers to remain in the round window niche, thus facilitating the precise local and directed delivery of loaded drugs. Based on these features, it is demonstrated here that n-acetylcysteine-loaded silk microcarriers have satisfactory antioxidant properties on cells and can successfully prevent NIHL in guinea pigs. These results indicate that the natural multifunctional silk microcarriers are promising agents for local inner ear drug delivery in the clinic., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Hair cells (HCs) in mammals cannot spontaneously regenerate after damage. Atoh1 overexpression can promote HC regeneration in the postnatal cochlea, but the regenerated HCs do not possess the structural and functional characteristics of HCs in situ. The stereocilia on the apical surface of HCs are the first-level structure for sound conduction, and regeneration of functional stereocilia is the key basis for the reproduction of functional HCs. Espin, as an actin bundling protein, plays an important role in the development and structural maintenance of the stereocilia. Here, we found that the upregulation of Espin by AAV-ie was able to induced the aggregation of actin fibres in Atoh1-induced HCs in both cochlear organoids and explants. In addition, we found that persistent Atoh1 overexpression resulted in impaired stereocilia in both endogenous and newly formed HCs. In contrast, the forced expression of Espin in endogenous and regenerative HCs was able to eliminate the stereocilia damage caused by persistent Atoh1 overexpression. Our study shows that the enhanced expression of Espin can optimize the developmental process of stereocilia in Atoh1-induced HCs and can attenuate the damage to native HCs induced by Atoh1 overexpression. These results suggest an effective method to induce the maturation of stereocilia in regenerative HCs and pave the way for functional HC regeneration via supporting cell transdifferentiation., (© 2023 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

Hearing impairment is a global health problem that affects social communications and the economy. The damage and loss of cochlear hair cells and spiral ganglion neurons (SGNs) as well as the degeneration of neurites of SGNs are the core causes of sensorineural hearing loss. Biotechnologies and biomedical engineering technologies provide new hope for the treatment of auditory diseases, which utilizes biological strategies or tissue engineering methods to achieve drug delivery and the regeneration of cells, tissues, and even organs. Here, the advancements in the applications of biotechnologies (including gene therapy and cochlear organoids) and biomedical engineering technologies (including drug delivery, electrode coating, electrical stimulation and bionic scaffolds) in the field of hearing reconstruction are presented. Moreover, we summarize the challenges and provide a perspective on this field., Competing Interests: The authors declare that there are no competing interests., (© 2023 The Authors. Smart Medicine published by Wiley‐VCH GmbH on behalf of Wenzhou Institute, University of Chinese Academy of Sciences.)

Hydroxycarboxylic acid receptor 2 (HCAR2), a member of Class A G-protein-coupled receptor (GPCR) family, plays a pivotal role in anti-lipolytic and anti-inflammatory effects, establishing it as a significant therapeutic target for treating dyslipidemia and inflammatory diseases. However, the mechanism underlying the signaling of HCAR2 induced by various types of ligands remains elusive. In this study, we elucidate the cryo-electron microscopy (cryo-EM) structure of G i -coupled HCAR2 in complex with a selective agonist, MK-6892, resolved to a resolution of 2.60 Å. Our structural analysis reveals that MK-6892 occupies not only the orthosteric binding pocket (OBP) but also an extended binding pocket (EBP) within HCAR2. Pharmacological assays conducted in this study demonstrate that the OBP is a critical determinant for ligand selectivity among the HCARs subfamily. Moreover, we investigate the pharmacological properties of the allosteric modulator compound 9n, revealing its probe-dependent behavior on HCAR2 in response to varying orthosteric agonists. Collectively, our findings provide invaluable structural insights that contribute to a deeper understanding of the regulatory mechanisms governing HCAR2 signaling transduction mediated by both orthosteric and allosteric ligands., (© 2023. West China Hospital, Sichuan University.)

Age-related hearing loss, or presbycusis, is a common cause of hearing loss in elderly people worldwide. It typically presents as progressive, irreversible, and usually affects the high frequencies of hearing, with a tremendous impact on the quality of life. Presbycusis is a complex multidimensional disorder, in addition to aging, multiple factors including exposure to noise, or ototoxic agents, genetic susceptibility, metabolic diseases and lifestyle can influence the onset and severity of presbycusis. With the aging of the body, its ability to clean up deleterious substances produced in the metabolic process is weakened, and the self-protection and repair function of the body is reduced, which in turn leads to irreversible damage to the cochlear tissue, resulting in the occurrence of presbycusis. Presently, oxidative stress (OS), mitochondrial DNA damage, low-grade inflammation, decreased immune function and stem cell depletion have been demonstrated to play a critical role in developing presbycusis. The purpose of this review is to illuminate the various mechanisms underlying this age-related hearing loss, with the goal of advancing our understanding, prevention, and treatment of presbycusis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yang, Zhao, Chai and Fan.)

Aminoglycoside antibiotics (AGAs) are widely used in life-threatening infections, but they accumulate in cochlear hair cells (HCs) and result in hearing loss. Increases in adenosine triphosphate (ATP) concentrations and P2X7 receptor expression were observed after neomycin treatment. Here, we demonstrated that P2X7 receptor, which is a non-selective cation channel that is activated by high ATP concentrations, may participate in the process through which AGAs enter hair cells. Using transgenic knockout mice, we found that P2X7 receptor deficiency protects HCs against neomycin-induced injury in vitro and in vivo. Subsequently, we used fluorescent gentamicin-Fluor 594 to study the uptake of AGAs and found fluorescence labeling in wild-type mice but not in P2rx7-/- mice in vitro. In addition, knocking-out P2rx7 did not significantly alter the HC count and auditory signal transduction, but it did inhibit mitochondria-dependent oxidative stress and apoptosis in the cochlea after neomycin exposure. We thus conclude that the P2X7 receptor may be linked to the entry of AGAs into HCs and is likely to be a therapeutic target for auditory HC protection., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The damage or degeneration of spiral ganglion neurons (SGNs) can impair the auditory signals transduction from hair cells to the central auditory system, and cause significant hearing loss. Herein, a new form of bioactive hydrogel incorporating topological graphene oxide (GO) and TEMPO-oxidized bacterial cellulose (GO/TOBC hydrogel) was developed to provide a favorable microenvironment for SGN neurite outgrowth. As the network structure of lamellar interspersed fiber cross-linked by GO/TOBC hydrogels well simulated the structure and morphology of ECM, with the controllable hydrophilic property and appropriate Young's modulus well met those requirements of SGNs microenvironment, the GO/TOBC hybrid matrix exhibited great potential to promote the growth of SGNs. The quantitative real-time PCR result confirmed that the GO/TOBC hydrogel can significantly accelerate the development of growth cones and filopodia, by increasing the mRNA expression levels of diap3, fscn2, and integrin β1. These results suggest that GO/TOBC hydrogel scaffolds have the potential to be used to construct biomimetic nerve grafts for repairing or replacing nerve defects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The peroxisome is a ubiquitous organelle in rodent cells and plays important roles in a variety of cell types and tissues. It is previously indicated that peroxisomes are associated with auditory function, and patients with peroxisome biogenesis disorders (PBDs) are found to have hearing dysfunction, but the specific role of peroxisomes in hearing remains unclear. In this study, two peroxisome-deficient mouse models (Atoh1-Pex5 -/- and Pax2-Pex5 -/- ) are established and it is found that peroxisomes mainly function in the hair cells of cochleae. Furthermore, peroxisome deficiency-mediated negative effects on hearing do not involve mitochondrial dysfunction and oxidative damage. Although the mammalian target of rapamycin complex 1 (mTORC1) signaling is shown to function through peroxisomes, no changes are observed in the mTORC1 signaling in Atoh1-Pex5 -/- mice when compared to wild-type (WT) mice. However, the expression of large-conductance, voltage-, and Ca2 + -activated K + (BK) channels is less in Atoh1-Pex5 -/- mice as compared to the WT mice, and the administration of activators of BK channels (NS-1619 and NS-11021) restores the auditory function in knockout mice. These results suggest that peroxisomes play an essential role in cochlear hair cells by regulating BK channels. Hence, BK channels appear as the probable target for treating peroxisome-related hearing diseases such as PBDs., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Dyslexia is a reading and spelling disorder due to neurodevelopmental abnormalities and is occasionally found to be accompanied by hearing loss, but the reason for the associated deafness remains unclear. This study finds that knockout of the dyslexia susceptibility 1 candidate 1 gene (Dyx1c1 -/- ) in mice, the best gene for studying dyslexia, causes severe hearing loss, and thus it is a good model for studying the mechanism of dyslexia-related hearing loss (DRHL). This work finds that the Dyx1c1 gene is highly expressed in the mouse cochlea and that the spontaneous electrical activity of inner hair cells and type I spiral ganglion neurons is altered in the cochleae of Dyx1c1 -/- mice. In addition, primary ciliary dyskinesia-related phenotypes such as situs inversus and disrupted ciliary structure are seen in Dyx1c1 -/- mice. In conclusion, this study gives new insights into the mechanism of DRHL in detail and suggests that Dyx1c1 may serve as a potential target for the clinical diagnosis of DRHL., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Hearing loss is one of the most common neurosensory disorders in humans, and above half of hearing loss is caused by gene mutations. Among more than 100 genes that cause non-syndromic hearing loss, myosin VI (MYO6) is typical in terms of the complexity of underlying mechanisms, which are not well understood. In this study, we used both knock-out (Myo6 -/- ) and point mutation (Myo6 C442Y ) mice as animal models, performed whole-cell patch-clamp recording and capacitance measurement in the inner hair cells (IHCs) in the cochlea, and sought to reveal potential functional and developmental changes in their ribbon synapses. In Myo6 -/- cochleae of both before (P8-10) and after hearing onset (P18-20), exocytosis from IHCs, measured in whole-cell capacitance change (ΔC m ), was significantly reduced, Ca 2+ current amplitude (I Ca ) was unchanged, but Ca 2+ voltage dependency was differently altered, causing significant increase in Ca 2+ influx in mature IHCs but not in immature IHCs. In immature IHCs of Myo6 C442Y/C442Y cochleae, neither ΔC m nor I Ca was altered, but both were reduced in mature IHCs of the same animal model. Furthermore, while the reduction of exocytosis was caused by a combination of the slower rate of depleting readily releasable (RRP) pool of synaptic vesicles and slower sustained release rate (SRR) in Myo6 -/- immature IHCs, it was likely due to smaller RRP and slower SRR in mature IHCs of both animal models. These results expand our understanding of the mechanisms of deafness caused by MYO6 mutations, and provide a solid theoretical and scientific basis for the diagnosis and treatment of deafness., (© 2023. The Author(s).)

Sensorineural hearing loss a result from hair cell damage, which is irreversible in mammals owing to the lack of hair cell regeneration, but recent researches have shown that Lgr5 + supporting cells are progenitors capable of regenerating hair cells. RPS14 (ribosomal protein S14) is a 40S ribosomal subunit component and is associated with erythrocyte differentiation, and in this study, we used a novel adeno-associated virus-inner ear system to upregulate Rps14 expression in cultured hair cell progenitors and observed an enhancement on their ability to proliferate and differentiate into hair cells. Similarly, Rps14 overexpression in the mice cochlea could promote supporting cells proliferation by activating the Wnt signalling pathway. In addition, over-expressing Rps14 induced hair cells regeneration in the organ of Corti, and lineage tracing showed that the new hair cells had transformed from Lgr5 + progenitors. In conclusion, our analysis reveals the potential role of Rps14 in driving hair cell regeneration in mammalian., (© 2023 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

The vascular system and the neural system processes occur simultaneously, the interaction among them is fundamental to the normal development of the central nervous system. Arid1a (AT-rich interaction domain 1A), which encodes an epigenetic subunit of the SWI/SNF chromatin-remodelling complex, is associated with promoter-mediated gene regulation and histone modification. However, the molecular mechanism of the interaction between cerebrovascular and neural progenitor cells (NPCs) remains unclear. To generate Arid1a cKO-Tie2 mice, Arid1a fl/fl mice were hybridized with Tie2-Cre mice. The Angiogenesis, neurogenesis and gliogenesis were studied by immunofluorescence staining and Western blotting. RNA-seq, RT-PCR, Western blotting, CO-IP and rescue experiments were performed to dissect the molecular mechanisms of Arid1a regulates fate determination of NPCs. We found that the absence of Arid1a results in increased the density of blood vessels, delayed neurogenesis and decreased gliogenesis, even after birth. Mechanistically, the deletion of Arid1a in endothelial cells causes a significant increase in H3k27ac and the secretion of maternal protein 2 (MATN2). In addition, matn2 alters the AKT/SMAD4 signalling pathway through its interaction with the NPCs receptor EGFR, leading to the decrease of SMAD4. SMAD complex further mediates the expression of downstream targets, thereby promoting neurogenesis and inhibiting gliogenesis. This study suggests that endothelial Arid1a tightly controls fate determination of NPCs by regulating the AKT-SMAD signalling pathway., (© 2023 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

Nerve injury caused by trauma or iatrogenic trauma can lead to loss of sensory and motor function, resulting in paralysis of patients. Inspired by endogenous bioelectricity and extracellular matrix, various external physical and chemical stimuli have been introduced to treat nerve injury. Benefiting from the self-power feature and great biocompatibility, piezoelectric biomaterials have attracted widespread attention in biomedical applications, especially in neural tissue engineering. Here, we provide an overview of the development of piezoelectric biomaterials for neural tissue engineering. First, several types of piezoelectric biomaterials are introduced, including inorganic piezoelectric nanomaterials, organic piezoelectric polymers, and their derivates. Then, we focus on the in vitro and in vivo external energy-driven piezoelectric effects involving ultrasound, mechanical movement, and other external field-driven piezoelectric effects. Neuroengineering applications of the piezoelectric biomaterials as in vivo grafts for the treatment of central nerve injury and peripheral nerve injury are also discussed and highlighted. Finally, the current challenges and future development of piezoelectric biomaterials for promoting nerve regeneration and treating neurological diseases are presented., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Smart Medicine published by Wiley‐VCH GmbH on behalf of Wenzhou Institute, University of Chinese Academy of Sciences.)

Progressive functional deterioration in the cochlea is associated with age-related hearing loss (ARHL). However, the cellular and molecular basis underlying cochlear aging remains largely unknown. Here, we established a dynamic single-cell transcriptomic landscape of mouse cochlear aging, in which we characterized aging-associated transcriptomic changes in 27 different cochlear cell types across five different time points. Overall, our analysis pinpoints loss of proteostasis and elevated apoptosis as the hallmark features of cochlear aging, highlights unexpected age-related transcriptional fluctuations in intermediate cells localized in the stria vascularis (SV) and demonstrates that upregulation of endoplasmic reticulum (ER) chaperon protein HSP90AA1 mitigates ER stress-induced damages associated with aging. Our work suggests that targeting unfolded protein response pathways may help alleviate aging-related SV atrophy and hence delay the progression of ARHL., (©The Author(s) 2022. Published by Oxford University Press on behalf of Higher Education Press.)

Spinal cord injury is a severe central nervous system injury, and developing appropriate drug delivery platforms for spinal nerve regeneration is highly anticipated. Here, we propose a basic fibroblast growth factor (bFGF)-loaded methacrylate gelatin (GelMA) hydrogel microsphere with ideal performances for spinal cord injury repair. Benefitting from the precise droplet manipulation capability of the microfluidic technology, the GelMA microspheres possess uniform and satisfactory size and good stability. More importantly, by taking advantage of the porous structures and facile chemical modification of the GelMA microspheres, bFGF could be easily loaded and gradually released. By co-culturing with neural stem cells, it is validated that the bFGF-loaded GelMA microspheres could effectively promote the proliferation and differentiation of neural stem cells. We also confirm the effective role of the bFGF-loaded GelMA microspheres in nerve repair of spinal cord injury in rats. Our results demonstrate the potential value of the microspheres for applications in repairing central nervous system injuries., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Luoran Shang is a member of the Smart Medicine editorial board., (© 2023 The Authors. Smart Medicine published by Wiley‐VCH GmbH on behalf of Wenzhou Institute, University of Chinese Academy of Sciences.)

Mitochondrial dynamics is essential for maintaining the physiological function of the mitochondrial network, and its disorders lead to a variety of diseases. Our previous study identified mitochondrial dynamics controlled anti-tumor immune responses and anxiety symptoms. However, how mitochondrial dynamics affects auditory function in the inner ear remains unclear. Here, we show that the deficiency of FAM73a or FAM73b, two mitochondrial outer membrane proteins that mediate mitochondrial fusion, leads to outer hair cells (HCs) damage and progressive hearing loss in FVB/N mice. Abnormal mitochondrial fusion causes elevated oxidative stress and apoptosis of HCs in the early stage. Thereafter, the activation of macrophages and CD4+ T cell is found in the mutant mice with the increased expression of the inflammatory cytokines IL-12 and IFN-γ compared with control mice. Strikingly, a dramatically decreased number of macrophages by Clophosome®-A-Clodronate Liposomes treatment alleviates the hearing loss of mutant mice. Collectively, our finding highlights that FAM73a or FAM73b deficiency affects HCs survival by disturbing the mitochondrial function, and the subsequent immune response in the cochleae worsens the damage of HCs., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Mechanosensitive hair cells (HCs) in the cochlear sensory epithelium are critical for sound detection and transduction. Mammalian HCs in the cochlea undergo cytogenesis during embryonic development, and irreversible damage to hair cells postnatally is a major cause of deafness. During the development of the organ of Corti, HCs and supporting cells (SCs) originate from the same precursors. In the neonatal cochlea, damage to HCs activates adjacent SCs to act as HC precursors and to differentiate into new HCs. However, the plasticity of SCs to produce new HCs is gradually lost with cochlear development. Here, we delineate an essential role for the guanine nucleotide exchange factor Net1 in SC trans-differentiation into HCs. Net1 overexpression mediated by AAV-ie in SCs promoted cochlear organoid formation and HC differentiation under two and three-dimensional culture conditions. Also, AAV-Net1 enhanced SC proliferation in Lgr5-EGFP CreERT2 mice and HC generation as indicated by lineage tracing of HCs in the cochleae of Lgr5-EGFP CreERT2 /Rosa26-tdTomato loxp/loxp mice. We further found that the up-regulation of Wnt/β-catenin and Notch signaling in AAV-Net1-transduced cochleae might be responsible for the SC proliferation and HC differentiation. Also, Net1 overexpression in SCs enhanced SC proliferation and HC regeneration and survival after HC damage by neomycin. Taken together, our study suggests that Net1 might serve as a potential target for HC regeneration and that AAV-mediated gene regulation may be a promising approach in stem cell-based therapy in hearing restoration., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Somatostatin receptor 2 (SSTR2) is highly expressed in neuroendocrine tumors and represents as a therapeutic target. Several peptide analogs mimicking the endogenous ligand somatostatin are available for clinical use, but poor therapeutic effects occur in a subset of patients, which may be correlated with subtype selectivity or cell surface expression. Here, we clarify the signal bias profiles of the first-generation peptide drug octreotide and a new-generation small molecule paltusotine by evaluating their pharmacological characteristics. We then perform cryo-electron microscopy analysis of SSTR2-Gi complexes to determine how the drugs activate SSTR2 in a selective manner. In this work, we decipher the mechanism of ligand recognition, subtype selectivity and signal bias property of SSTR2 sensing octreotide and paltusotine, which may aid in designing therapeutic drugs with specific pharmacological profiles against neuroendocrine tumors., (© 2023. The Author(s).)