Hainan Lang, M.D., Ph.D.
Cellular and Molecular Mechanisms of Sensorineural Hearing Loss
Genetically modified mouse models and human inner ear tissues have been used for understanding the cellular and molecular mechanisms of auditory nerve survival and degeneration in several pathological conditions, including aging, exposure to noise and ototoxic drugs, and genetic defects. We focus on the functional roles of neural crest cell associated transcription factors, RNA binding proteins, the complement system, and their related regulatory networks for enhancing remyelination, preventing or protecting the auditory nerve from degeneration, and promoting functional recovery after cochlear injury. This research includes (1) cutting-edge cellular and molecular procedures in hearing research such as molecular imaging of living cochlear cells, 3D cell culture assay, RT-qPCR, NanoString and RNA-seq analysis of the degenerative auditory nerve; (2) collection and examination of mouse and human temporal bone tissues; (3) contemporary histopathological and high-resolution imaging techniques to assay human and animal inner ear specimens; and 4) evaluation of auditory function using electrophysiological techniques including the measurement of auditory nerve compound action potentials, spontaneous activities of single auditory nerve fibers, and auditory brainstem responses. The study has been supported by grants from NIH/NIDCD for more than 10 years (Lang PI).
Adult Stem/Progenitor Cell and Auditory Nerve Regeneration/Repair
Our recent research on isolation and characterization of adult neural stem/progenitor cells from the adult mouse auditory nerve is aimed at replacing damaged spiral ganglion neurons (SGNs), preventing SGN degeneration and promoting auditory functional recovery. Several lines of studies are ongoing with a focus on remyelination and de-differentiation of adult glial cells after acute auditory nerve injury resulting from noise- or ototoxic drug-exposure. A variety of advanced methods are employed to 1) isolate and expand neural stem/progenitor cells using neurosphere culture assay and auditory nerve micro-dissection; 2) purify and characterize neural stem/progenitor cells using transgenic mouse models and fluorescence-activated cell sorting; 3) identify the molecular characteristics of neural stem/progenitor cells using next generation sequencing, gene expression profiling at the single cell level (e.g., single cell RNA-seq), complementary proteomics assays and super resolution imaging analysis; and 4) directly evaluating functional integration of the transplanted stem cells using microsurgery and well-established mouse models of auditory nerve degeneration. The study has been supported by grants from NIH/NIDCD for more than 14 years (Lang PI).
Peripheral Auditory System Deficits and Autism-Like Behaviors
This is an exciting and newly developed project, which addresses a novel hypothesis that abnormal macrophage related activities, resulting from gene deficiency, lead to hearing loss and these changes may be associated with communication impairment in Autism Spectrum Disorder and other neurodevelopmental disorders. For example, mutations or deletions in the MEF2C gene has recently been linked to Autism Spectrum Disorder. In collaboration with Dr. Christopher Cowan from the Department of Neuroscience and Dr. Bärbel Rohrer from the Department of Ophthalmology, our experiments revealed that Mef2c is highly expressed in cochlear macrophages in postnatal mice and that Mef2c hypofunction results in auditory nerve functional decline and hearing loss. This research is now supported by a research grant from Simmons Foundation (SFARI Pilot Award; MPI; Cowan/Lang/Roehrer).
Selected Recent Publications
- Liu T, Li G, Noble KV, Li Yong, Barth JL, Schulte BA, Lang H. Age-Dependent Alterations of Kir4.1 Expression in Neural Crest-Derived Cells of the Mouse and Human Cochlea. Neurobiol Aging. 2019; 80:210. PMCID: PMC6679794
- Noble KV, Liu T, Matthews L, Schulte BA, Lang H. Age-Related Alterations in Resident Immune Cells of the Human Cochlea. Front Neurol. 2019; 10:895. PMCID: PMC6707808
- Noble KV, Reyzer ML, Barth JL, McDonald H, Tuck M, Schey KL, Krug EL, Lang H. Use of Proteomic Imaging Coupled with Transcriptomic Analysis to Identify Biomolecules Responsive to Cochlear Injury. Front Mol Neurosc. 2018; 11:243. PMCID: PMC6056684
- Panganiban CH, Barth JL, Darbelli L, Xing Y, Zhang J, Li H, Noble KV, Liu T, Brown LN, Schulte BA, Richard S, Lang H. Noise-Induced Dysregulation of Quaking RNA Binding Proteins Contributes to Auditory Nerve Demyelination and Hearing Loss. J Neurosci. 2018; 38:2551-2568. PMCID: PMC5858596
- Brown LN, Xing Y, Noble KV, Barth JL, Panganiban CH, Smythe NM, Bridges MC, Zhu J, Lang H. Macrophage-Mediated Glial Cell Elimination in the Postnatal Mouse Cochlea. Front Mol Neurosc. 2017; 10:407. PMCID: PMC5770652
- Lang H, Nishimoto E, Xing Y, Brown LN, Noble KV, Barth JL, LaRue AC, Ando K, Schulte BA. Contributions of Mouse and Human Hematopoietic Cells to Remodeling of the Adult Auditory Nerve After Neuron Loss. Mol Ther. 2016; 24:2000. PMCID: PMC5154482
- Lang H, Xing Y, Brown LN, Samuvel DJ, Panganiban CH, Havens LT, Balasubramanian S, Wegner M, Krug EL, Barth JL. Neural Stem/Progenitor Cell Properties of Glial Cells in the Adult Mouse Auditory Nerve. Sci Rep. 2015; 5:13383. PMCID: PMC4549618
- Hao X, Xing Y, Moore MW, Zhang J, Han D, Schulte BA, Dubno JR, Lang H. Sox10 Expressing Cells in the Lateral Wall of the Aged Mouse and Human Cochlea. PloS One. 2014; 9:e97389. PMCID: PMC4041576
- Stevens SM, Xing Y, Hensley CT, Zhu J, Dubno JR, Lang H. Heptanol Application to the Mouse Round Window: a Model for Studying Cochlear Lateral Wall Regeneration. Otolaryngol Head Neck Surg. 2014; 150:659. PMCID: PMC4090013
- Yuan Y, Shi F, Yin Y, Tong M, Lang H, Polley DB, Liberman MC, Edge AS. Ouabain-Induced Cochlear Nerve Degeneration: Synaptic Loss and Plasticity in a Mouse Model of Auditory Neuropathy. J Assoc Res Otolaryngol. 2014; 15:31. PMCID: PMC3901858
The journey is more important than the endpoint. In science or life, little time is spent at 28,000 feet.
— Louis Reichardt