Transcriptome-Wide Analysis Reveals a Role for Extracellular Matrix and Integrin Receptor Genes in Otic Neurosensory Differentiation from Human iPSCs

Abstract

We analyzed transcriptomic data from otic sensory cells differentiated from human induced pluripotent stem cells (hiPSCs) by a previously described method to gain new insights into the early human otic neurosensory lineage. We identified genes and biological networks not previously described to occur in the human otic sensory developmental cell lineage. These analyses identified and ranked genes known to be part of the otic sensory lineage program (SIX1, EYA1, GATA3, etc.), in addition to a number of novel genes encoding extracellular matrix (ECM) (COL3A1, COL5A2, DCN, etc.) and integrin (ITG) receptors (ITGAV, ITGA4, ITGA) for ECM molecules. The results were confirmed by quantitative PCR analysis of a comprehensive panel of genes differentially expressed during the time course of hiPSC differentiation in vitro. Immunocytochemistry validated results for select otic and ECM/ITG gene markers in the in vivo human fetal inner ear. Our screen shows ECM and ITG gene expression changes coincident with hiPSC differentiation towards human otic neurosensory cells. Our findings suggest a critical role of ECM-ITG interactions with otic neurosensory lineage genes in early neurosensory development and cell fate determination in the human fetal inner ear.

Single cell RNA sequencing analysis of mouse cochlear supporting cell transcriptomes with activated ERBB2 receptor, a candidate mediator of cochlear regeneration mechanisms

“…Importance of ERBB2-mediated ECM modulation for hair cells regeneration is also supported by recent studies indicating that extracellular matrix and integrin receptors are induced in early neurosensory development and cell fate determination in the human fetal inner ear 72 . We speculate that enforced activation of signaling pathways through ERBB family receptors might allow for changes in the environment of the organ of Corti that promote the proliferation of supporting cells and permit the regeneration of hair cells.…”

Time-resolved quantitative proteomic analysis of the developing Xenopus otic vesicle reveals putative congenital hearing loss candidates

“…ECM proteins also increase during hair cell differentiation from human iPSCs. 58 Our Xenopus data reveal a number of collagens and other ECM proteins that dynamically increase during the course of otic development, specifically at stages 45 and 47 with a >4-fold increase in abundance as compared to stage 34. These included ECM proteins such as Lum, Mfap2, and Hapln1 among others that are putative downstream targets of human CHL genes.…”

hiPSC-Derived Cells as Models for Drug Discovery 2.0

“…Johnson Chacko et al [ 14 ] describe the role of the extracellular matrix and integrin receptor genes in human iPSC-derived otic neurosensory differentiation. They identify the critical role of novel gene encoding of the extracellular matrix and integrin receptor interactions with otic neurosensory lineage genes in early neurosensory development and cell fate determination in the human fetal inner ear.…”