Jiaoyao Ma

Eye & ENT Hospital of Fudan University

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Shan Sun

Eye & ENT Hospital of Fudan University

Wenyan Li

State Key Laboratory of Medical Neurobiology

Mingyu Xia

Eye & ENT Hospital of Fudan University

Huawei Li

Eye & ENT Hospital of Fudan University

Renjie Chai

Southeast University

Gaogan Jia

Eye & ENT Hospital of Fudan University

Luo Guo

Eye & ENT Hospital of Fudan University

Yaoqian Liu

Eye & ENT Hospital of Fudan University

Mingxuan Wu

Westlake University

Yiyun Lou

Eye & ENT Hospital of Fudan University

Cooperative Institutions

Eye & ENT Hospital of Fudan University

State Key Laboratory of Medical Neurobiology

Fudan University

Shanghai Center for Brain Science and Brain-Inspired Technology

National Health and Family Planning Commission

Zhejiang University

Anhui Medical University

Nanjing Medical University

Shanghai Medical College of Fudan University

Jilin University

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Integration of Functional Human Auditory Neural Circuits Based on a 3D Carbon Nanotube System (Adv. Sci. 32/2024)

Advanced Science (2024)

Yiyun Lou Jiaoyao Ma Yangnan Hu Xiaoying Yao Yaoqian Liu

Biological neural network

10.1002/advs.202470191

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Citations (0)

P2X7 receptor is required for the ototoxicity caused by aminoglycoside in developing cochlear hair cells

Neurobiology of Disease (2023)

Cheng Cheng Jiaoyao Ma Xiaoling Lu Panpan Zhang Xiaohan Wang

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.

Ototoxicity

Neomycin

Adenosine triphosphate

10.1016/j.nbd.2023.106176

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Citations (5)

Loss of Mst1/2 activity promotes non-mitotic hair cell generation in the neonatal organ of Corti

npj Regenerative Medicine (2022)

Xiaoling Lu Huiqian Yu Jiaoyao Ma Kunkun Wang Luo Guo

Mammalian sensory hair cells (HCs) have limited capacity for regeneration, which leads to permanent hearing loss after HC death. Here, we used in vitro RNA-sequencing to show that the Hippo signaling pathway is involved in HC damage and self-repair processes. Turning off Hippo signaling through Mst1/2 inhibition or Yap overexpression induces YAP nuclear accumulation, especially in supporting cells, which induces supernumerary HC production and HC regeneration after injury. Mechanistically, these effects of Hippo signaling work synergistically with the Notch pathway. Importantly, the supernumerary HCs not only express HC markers, but also have cilia structures that are able to form neural connections to auditory regions in vivo. Taken together, regulating Hippo suggests new strategies for promoting cochlear supporting cell proliferation, HC regeneration, and reconnection with neurons in mammals.

Hippo signaling pathway

10.1038/s41536-022-00261-4

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Integration of Functional Human Auditory Neural Circuits Based on a 3D Carbon Nanotube System

Advanced Science (2024)

Yiyun Lou Jiaoyao Ma Yangnan Hu Xiaoying Yao Yaoqian Liu

Abstract 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.

Biological neural network

Auditory System

Calcium imaging

10.1002/advs.202309617

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Citations (3)

MEK/ERK signaling drives the transdifferentiation of supporting cells into functional hair cells by modulating the Notch pathway

Stem Cells Translational Medicine (2024)

Jiaoyao Ma Mingyu Xia Jin Guo Wen Li Shan Sun

Abstract Loss of cochlear hair cells (HCs) leads to permanent hearing loss in mammals, and regenerative medicine is regarded as an ideal strategy for hearing recovery. Limited genetic and pharmaceutical approaches for HC regeneration have been established, and the existing strategies cannot achieve recovery of auditory function. A promising target to promote HC regeneration is MEK/ERK signaling because dynamic shifts in its activity during the critical stages of inner ear development have been observed. Here, we first showed that MEK/ERK signaling is activated specifically in supporting cells (SCs) after aminoglycoside-induced HC injury. We then selected 4 MEK/ERK signaling inhibitors, and PD0325901 (PD03) was found to induce the transdifferentiation of functional supernumerary HCs from SCs in the neonatal mammalian cochlear epithelium. We next found that PD03 facilitated the generation of HCs in inner ear organoids. Through genome-wide high-throughput RNA sequencing and verification, we found that the Notch pathway is the downstream target of MEK/ERK signaling. Importantly, delivery of PD03 into the inner ear induced mild HC regeneration in vivo. Our study thus reveals the importance of MEK/ERK signaling in cell fate determination and suggests that PD03 might serve as a new approach for HC regeneration.

Transdifferentiation

10.1093/stcltm/szae030

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Auditory Neural Plasticity in Tinnitus Mechanisms and Management

Neural Plasticity (2020)

Kunkun Wang Dongmei Tang Jiaoyao Ma Shan Sun

Tinnitus, which is the perception of sound in the absence of a corresponding external acoustic stimulus, including change of hearing and neural plasticity, has become an increasingly important ailment affecting the daily life of a considerable proportion of the population and causing significant burdens for both the affected individuals and society as a whole. Here, we briefly review the epidemiology and classification of tinnitus, and the currently available treatments are discussed in terms of the available evidence for their mechanisms and efficacy. The conclusion drawn from the available evidence is that there is no specific medication for tinnitus treatment at present, and tinnitus management might provide better solutions. Therapeutic interventions for tinnitus should be based on a comprehensive understanding of the etiology and features of individual cases of tinnitus, and more high quality and large-scale research studies are urgently needed to develop more efficacious medications.

Etiology

10.1155/2020/7438461

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The Role of Autoimmunity in the Pathogenesis of Sudden Sensorineural Hearing Loss

Neural Plasticity (2018)

Guangfei Li Dan You Jiaoyao Ma Wen Li Huawei Li

Sudden sensorineural hearing loss (SSHL) is a clinically common acute symptom in otolaryngology. Although the incidence of SSHL has increased around the world in recent years, the etiology of the disease is still unclear. It has been reported that infections, ototoxic drugs, membrane labyrinth rupture, carcinomas, circulatory system diseases, autoimmune diseases, brain lesions, mental diseases, congenital or inherited diseases, and so on, are all risk factors for SSHL. Here, we discuss the autoimmune mechanisms behind SSHL, which might be induced by type II–IV allergic reactions. We also introduce the main immunosuppressive medications that have been used to treat SSHL, which will help us to identify potential targets for immune therapy.

Etiology

Pathogenesis

10.1155/2018/7691473

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Citations (48)

Bone morphogenetic proteins and inner ear development

Journal of Zhejiang University SCIENCE B (2018)

Jiaoyao Ma Dan You Wenyan Li Xiaoling Lü Shan Sun

Subfamily

Limb development

10.1631/jzus.b1800084

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Citations (9)

Selective ablation of inner hair cells and subsequent in-situ hair cell regeneration in the neonatal mouse cochlea

Hearing Research (2021)

Mingyu Xia Mingxuan Wu Liping Zhao Jiaoyao Ma Wenyan Li

Loss of hair cells (HCs) accounts for most sensorineural hearing loss, and regeneration of cochlear HCs is considered as the ultimate strategy for restoring hearing. Several lines of evidence have shown that Lgr5+ progenitor cells can spontaneously regenerate new HCs after HC loss at the neonatal stage, and most of which are immature. IHCs are resistant to ototoxic drugs and noise and cannot be ablated efficiently in order to precisely investigate IHC regeneration in existing hearing injury models, and thus we generated a new transgenic mouse model by inserting diphtheria toxin receptor (DTR) under the control of the Vglut3 promoter. In this model, IHCs were selectively ablated in a dose-dependent manner after the injection of diphtheria toxin (DT) at the neonatal stage, while OHCs remained intact with normal hair bundle structures until adulthood. With this IHC-specific injury model, we observed HC regeneration from Lgr5+ progenitors after IHC ablation at the neonatal stage. Some of the newly generated HCs replaced the lost IHCs in-situ and re-build the structure of the organ of Corti through the asymmetrical mitosis of progenitor cells. While, the majority of the regenerated HCs did not survive until adulthood, and the loss of spiral ganglion neurons was observed after the IHC ablation, which led to profound hearing loss after DT injection in Vglut3DTR+ mice at the neonatal stage. The model presented here shows promise for investigating the mechanisms behind IHC loss and subsequent regeneration.

Spiral ganglion

Progenitor

Ototoxicity

10.1016/j.heares.2021.108275

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Citations (7)

Generation of innervated cochlear organoid recapitulates early development of auditory unit

Stem Cell Reports (2022)

Mingyu Xia Jiaoyao Ma Mingxuan Wu Luo Guo Yan Chen

Functional cochlear hair cells (HCs) innervated by spiral ganglion neurons (SGNs) are essential for hearing, whereas robust models that recapitulate the peripheral auditory circuity are still lacking. Here, we developed cochlear organoids with functional peripheral auditory circuity in a staging three-dimensional (3D) co-culture system by initially reprogramming cochlear progenitor cells (CPCs) with increased proliferative potency that could be long-term expanded, then stepwise inducing the differentiation of cochlear HCs, as well as the outgrowth of neurites from SGNs. The function of HCs and synapses within organoids was confirmed by a series of morphological and electrophysiological evaluations. Single-cell mRNA sequencing revealed the differentiation trajectories of CPCs toward the major cochlear cell types and the dynamic gene expression during organoid HC development, which resembled the pattern of native HCs. We established the cochlear organoids with functional synapses for the first time, which provides a platform for deciphering the mechanisms of sensorineural hearing loss.

Organoid

Cochlear Implantation

10.1016/j.stemcr.2022.11.024

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Citations (20)