Duncan R Keith, Liu Liqian, Moyer Mo, Wylie Andrew, Dano Ranya, Cassinotti Luis
Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, USA.
Department of Otolaryngology - Head and Neck Surgery, Kresge Hearing Research Institute, University of Michigan, Ann Arbor, MI USA.
bioRxiv. 2025 Mar 21:2025.03.21.644434. doi: 10.1101/2025.03.21.644434.
Inner ear organoid development-from germ layer to otocyst formation-relies on timed chemical cues to recapitulate major signals . In contrast, later stages of differentiation-from otic vesicle (OV) to organoid formation-are self-guided, even though these stages are modulated by several key morphogens . We sought to elucidate additional morphogens that might improve culture efficiency and influence cell fate decisions. Using a whole-transcriptomic approach, we identified major differences in native and stem cell-derived OVs related to anterior-posterior patterning and retinoic acid (RA) signaling. Increasing the level of RA during OV formation in these cultures modulated organoid efficiency, increased nonsensory markers, decreased sensory markers, and decreased hair cell production. The organoid culture platform mimics the exquisite RA sensitivity found in normal inner ear development and may help identify RA-responsive genes driving organogenesis and cell fate specification.
内耳类器官的发育——从胚层到耳泡形成——依赖于定时的化学信号来重现主要信号。相比之下，分化的后期阶段——从耳泡（OV）到类器官形成——是自我引导的，尽管这些阶段受到几种关键形态发生素的调节。我们试图阐明可能提高培养效率并影响细胞命运决定的其他形态发生素。使用全转录组学方法，我们确定了天然和干细胞来源的耳泡在前后模式和视黄酸（RA）信号传导方面的主要差异。在这些培养物的耳泡形成过程中提高RA水平可调节类器官效率，增加非感觉标记物，减少感觉标记物，并减少毛细胞产生。类器官培养平台模拟了正常内耳发育中发现的对RA的高度敏感性，可能有助于识别驱动器官发生和细胞命运特化的RA反应基因。
