Chemically defined and dynamic click hydrogels support hair cell differentiation in human inner ear organoids

Stem Cell Reports, Journal Year: 2025, Volume and Issue: unknown, P. 102386 - 102386

Published: Jan. 1, 2025

Highlights•Multifunctional, dynamic hydrogels display highly tunable mechanical properties•Gel stiffness influences inner ear organoid viability and otic vesicle formation•Dynamic permit the generation of authentic progenitor cells•Encapsulated progenitors give rise to later-stage cell populationsSummaryThe properties in microenvironment play a key role its patterning during embryonic development. To recapitulate development vitro, three-dimensional tissue engineering strategies including application representative models scaffolds are increasing interest. Human organoids promising model developmental processes; however, current protocol requires Matrigel that contains ill-defined extracellular matrix components. Here, we implement an alternative, chemically defined, hydrogel support differentiation human organoids. Specifically, thiol-norbornene hydrazide-aldehyde click chemistries used fabricate organoid-laden, gelatin-based scaffolds. We identify optimal formulations hair with comparable efficiency fidelity Matrigel-cultured These results suggest defined may serve as viable alternative for engineering.Graphical abstract

Language: Английский

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Regeneration of sensory hair cells in mature mammals

Current topics in developmental biology/Current Topics in Developmental Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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β-Catenin is required for radial cell patterning and identity in the developing mouse cochlea

Proceedings of the National Academy of Sciences, Journal Year: 2019, Volume and Issue: 116(42), P. 21054 - 21060

Published: Sept. 30, 2019

Significance The cochlea is essential for sound detection. It consists of highly differentiated hair cells and nonsensory supporting radially patterned into lateral medial compartments. However, mechanisms regulating radial patterning specification cell subtypes, each which serves unique functions, are unclear. Here we show that β-catenin required differentiation sensory subtypes in the developing cochlea. β-Catenin-deleted cochleae displayed disrupted compartment borders containing ectopic whereas inhibiting transcriptional preserving adhesion-mediated activities maintained identity. This study thus characterizes a role β-catenin-mediated adhesion

Language: Английский

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Interplay Between Notch and YAP/TAZ Pathways in the Regulation of Cell Fate During Embryo Development

Frontiers in Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 9

Published: Aug. 19, 2021

Cells in growing tissues receive both biochemical and physical cues from their microenvironment. Growing evidence has shown that mechanical signals are fundamental regulators of cell behavior. However, how properties the microenvironment transduced into critical behaviors, such as proliferation, progenitor maintenance, or differentiation during development, is still poorly understood. The transcriptional co-activators YAP/TAZ shuttle between cytoplasm nucleus response to multiple inputs have emerged important tissue growth regeneration. sense transduce cues, those extracellular matrix actomyosin cytoskeleton, regulate gene expression, thus allowing them function gatekeepers behavior several developmental contexts. Notch pathway a key signaling controls binary fate decisions through cell–cell communication context-dependent manner. Recent reports now suggest crosstalk these two pathways for maintaining balance maintenance different tissues. How this integrates with morphogenesis changes architecture development an open question. Here, we discuss specification, coordinated construct functional organ. We will pay special attention interplay determining whether represents general mechanism regulating development. focus on research carried out vertebrate embryos demonstrate roles stem biology future challenges.

Language: Английский

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SoxC transcription factors shape the epigenetic landscape to establish competence for sensory differentiation in the mammalian organ of Corti

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(34)

Published: Aug. 16, 2023

The auditory organ of Corti is comprised only two major cell types—the mechanosensory hair cells and their associated supporting cells—both specified from a single pool prosensory progenitors in the cochlear duct. Here, we show that competence to respond Atoh1, transcriptional master regulator necessary sufficient for induction cells, established between E12.0 13.5. transition competent state rapid with extensive remodeling epigenetic landscape controlled by SoxC group transcription factors. Conditional loss Sox4 Sox11 —the homologous family members transiently expressed inner ear at time establishment—blocks ability differentiate as cells. Mechanistically, binds establishes accessibility early sensory lineage–specific regulatory elements, including ones Atoh1 its direct downstream targets. Consistent these observations, overexpression or prior developmental establishment precociously induces differentiation progenitors. Further, reintroducing expression restores postnatal vitro vivo. Our findings demonstrate pivotal role agents changes establishing receptor ear.

Language: Английский

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Ptch1 is essential for cochlear marginal cell differentiation and stria vascularis formation

Cell Reports, Journal Year: 2024, Volume and Issue: 43(4), P. 114083 - 114083

Published: April 1, 2024

A common cause of deafness in humans is dysregulation the endocochlear potential generated by stria vascularis (SV). Thus, proper formation SV critical for hearing. Using single-cell transcriptomics and a series Shh signaling mutants, we discovered that receptor Patched1 (Ptch1) essential marginal cell (MC) differentiation formation. Single-cell RNA sequencing analyses revealed cochlear roof epithelium already specified into discrete domains with distinctive gene expression profiles at embryonic day 14, Gsc as marker MC lineage. Ptch1 deficiency leads to defective specification precursors along basal-apical regions. We demonstrated elevated Gli2 levels impede through sustaining Otx2 maintaining progenitor state precursors. Our results uncover an early non-sensory epithelial cells establish crucial role Ptch1-Gli2 axis regulating development SV.

Language: Английский

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The Hippo pathway and p27 ^Kip1 cooperate to suppress mitotic regeneration in the organ of Corti and the retina

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(14)

Published: April 3, 2025

The mature mammalian auditory sensory organ, the organ of Corti (OC), lacks capacity for regenerating hair cells, leading to permanent hearing impairment. In contrast, vestibular system has a limited cell regeneration, which we have shown be further enhanced by inhibiting Hippo pathway. Here, demonstrate that, despite similar transcriptional responses, only and not supporting cells proliferate as result Yap activation following inhibition. Mechanistically, identify p27 Kip1 , cycle kinase inhibitor encoded Cdkn1b an additional barrier preventing reentry specifically in OC. We show that while both systems stimulates degradation through its direct target gene Skp2 this protein-level control is antagonized unusually high level transcription cochlea. Consequently, activity maintained OC even presence constitutively active Yap5SA, counteracting mitogenic effects. Supporting model, inactivation pathway -deficient background sufficient induce adult proliferation vivo. Furthermore, synergistic interaction between conserved retina where inhibition pathways potently induces Müller glia initiates neuronal regeneration. Our work uncovers molecular mechanism quiescent progenitor ear eye, from reentering after damage—the key step toward receptor regeneration blocked mammals.

Language: Английский

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Initiation of Supporting Cell Activation for Hair Cell Regeneration in the Avian Auditory Epithelium: An Explant Culture Model

Frontiers in Cellular Neuroscience, Journal Year: 2020, Volume and Issue: 14

Published: Nov. 12, 2020

Sensorineural hearing loss is a common disability often caused by the of sensory hair cells in cochlea. Hair cell (HCs) regeneration has long been main target for development novel therapeutics sensorineural loss. In mammalian cochlea, limited, but auditory epithelia non-mammalian organisms retain capacity regeneration. avian basilar papilla (BP), supporting (SCs), which give rise to regenerated cells, are usually quiescent. induces both direct transdifferentiation and mitotic division cells. Here, we established an explant culture model chick papillae validated it investigating initial phase The histological assessment demonstrated via Labeling with 5-ethynyl-2'-deoxyuridine (EdU) revealed occurrence at specific locations papillae, while no EdU labeling was observed newly generated RNA sequencing indicated alterations known signaling pathways associated regeneration, consistent previous findings. Also, unbiased analyses data genes that may be related induction activation papillae. These results indicate advantages our exploring molecular mechanisms

Language: Английский

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The noncoding genome and hearing loss

Human Genetics, Journal Year: 2021, Volume and Issue: 141(3-4), P. 323 - 333

Published: Sept. 7, 2021

Language: Английский

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The mechanical forces that shape our senses

Development, Journal Year: 2022, Volume and Issue: 149(7)

Published: March 31, 2022

ABSTRACT Developing organs are shaped, in part, by physical interaction with their environment the embryo. In recent years, technical advances live-cell imaging and material science have greatly expanded our understanding of mechanical forces driving organ formation. Here, we provide a broad overview types generated during embryonic development then focus on subset underlying senses: eyes, inner ears, nose skin. The epithelia these emerge from common origin: ectoderm germ layer; yet, they arrive at unique complex forms over developmental time. We discuss exciting animal studies that show crucial role for in, example, thickening sensory placodes, coiling cochlea lengthening hair. Finally, how microfabricated organoid systems can now unprecedented insights into principles human development.

Language: Английский

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