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Engineering multi-lineage human inner ear organoids

工程多谱系人类内耳类器官

基本信息

批准号：
10531197
负责人：
Karl Russell Koehler
金额：
$ 51.13万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10531197
关键词：
Afferent Neurons Biopsy Bone Morphogenetic Proteins Brain Cell Line Cell Lineage Cells Chemical Engineering Chemicals Cochlea Communities Cyst Data Data Set Dependence Development Developmental Biology Disease Dizziness Ectoderm Embryo Embryonic Development Engineering Ensure Epithelium Equilibrium Female Fibroblast Growth Factor Future Gene Expression Profile Genetic Diseases Genetic Models Goals Growth Factor Hair Cells Hearing Histologic Human Hydrogels In Vitro Investigation Laboratories Laboratory Research Labyrinth Maps Mesenchymal Mesoderm Methods Modeling Molecular Monitor Mus Natural regeneration Neuroglia Neurons Organ Organoids Otic Vesicle Otolaryngology Patients Pattern Pharmacotherapy Physiology Production Protocols documentation Reporter Reporting Reproducibility Research Research Personnel SHH gene Sensory Sensory Hair Shapes Signal Pathway Signal Transduction Synapses System Technology Transfer Testing Therapeutic Time Tissue Microarray Tissues Transforming Growth Factors Tretinoin WNT Signaling Pathway Work cell type design directed differentiation drug discovery drug testing experimental study gene therapy hearing impairment human pluripotent stem cell improved in vivo induced pluripotent stem cell inner ear development inner ear diseases insight male matrigel microphysiology system next generation non-invasive monitor real time monitoring self assembly sensory system single cell analysis single-cell RNA sequencing stem cells synaptogenesis technological innovation three dimensional cell culture tool

项目摘要

ABSTRACT Inner ear development requires the assembly of diverse cells from multiple embryonic lineages. The epithelial, neuronal, and glial components of the inner ear are ectoderm-derived, whereas the mesenchymal components are predominantly mesoderm-derived. A major engineering challenge is to establish multi-lineage inner ear tissues in vitro, which researchers could use to study human hearing and balance-related diseases, investigate developmental biology questions, and evaluate promising therapeutics. The routine use of patient-derived inner ear explants for research is not feasible because the human inner ear is difficult to biopsy. Therefore, our long-term goal is to define the chemical and physical signals required to recapitulate formation of functional human inner ear tissue in vitro from human pluripotent stem cells (hPSCs). This project builds upon a recent technological innovation reported by our laboratory: a multi-stage 3D culture system for generating inner ear organoids that contain sensory hair cells and neurons. Despite significant progress, there are remaining questions about how faithfully inner ear organoids mimic normal embryonic development. Moreover, there are technical hurdles that may limit integration of inner ear organoids into tissue-chip drug discovery platforms. Specifically, organoid production efficiency is variable and the full range of cell types in organoids is unclear. Moreover, our ability to track the development or physiology of inner ear sensory cells in real-time is limited. Our research plan will define a next-generation inner ear organoid system. For Aim 1, we will use high- throughput single-cell analysis to generate a cell fate map of developing inner ear organoids. In Aim 2, we will generate dual-reporter hPSC lines for real-time monitoring of inner ear organoid sensorineural networks. In Aim 3, we will engineer chemically-defined inner ear organoids with improved fidelity to mammalian development. Finally, we will verify inner ear organoid production from a set of four human induced pluripotent stem cell lines to ensure the reproducibility of our results. Together, completion of this project will deepen our characterization of the human inner ear organoid model and facilitate transfer of the technology to other research laboratories. Future investigations could pursue unexplored cell signaling mechanisms, model genetic diseases, or integrate organoids into tissue-chip systems. We anticipate that our study will provide broadly applicable insights that should aid the production of organoids of other sensory systems and should provide a powerful tool for otolaryngology research.

摘要

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Hair-bearing human skin generated entirely from pluripotent stem cells.

DOI：
10.1038/s41586-020-2352-3
发表时间：
2020-06
期刊：
Nature
影响因子：
64.8
作者：
Lee J;Rabbani CC;Gao H;Steinhart MR;Woodruff BM;Pflum ZE;Kim A;Heller S;Liu Y;Shipchandler TZ;Koehler KR
通讯作者：
Koehler KR

A single-cell level comparison of human inner ear organoids with the human cochlea and vestibular organs.

DOI：
10.1016/j.celrep.2023.112623
发表时间：
2023-06-27
期刊：
Cell reports
影响因子：
8.8
作者：
通讯作者：

Building inner ears: recent advances and future challenges for in vitro organoid systems.

DOI：
10.1038/s41418-020-00678-8
发表时间：
2021-01
期刊：
Cell death and differentiation
影响因子：
12.4
作者：
van der Valk WH;Steinhart MR;Zhang J;Koehler KR
通讯作者：
Koehler KR

Dynamic Click Hydrogels for Xeno-Free Culture of Induced Pluripotent Stem Cells.

DOI：
10.1002/adbi.202000129
发表时间：
2020-11
期刊：
Advanced biosystems
影响因子：
4.1
作者：
Arkenberg MR;Dimmitt NH;Johnson HC;Koehler KR;Lin CC
通讯作者：
Lin CC

Generation and characterization of hair-bearing skin organoids from human pluripotent stem cells.

DOI：
10.1038/s41596-022-00681-y
发表时间：
2022-05
期刊：
NATURE PROTOCOLS
影响因子：
14.8
作者：
Lee, Jiyoon;van der Valk, Wouter H.;Serdy, Sara A.;Deakin, CiCi;Kim, Jin;Le, Anh Phuong;Koehler, Karl R.
通讯作者：
Koehler, Karl R.