Cell size regulates human endoderm specification through actomyosin-dependent AMOT-YAP signaling

• Published in: Stem cell reports 2024-08, Vol.19 (8), p.1137-1155
• Main Authors: Jiang, Lai, Yan, Chenchao, Yi, Ying, Zhu, Lihang, Liu, Zheng, Zhang, Donghui, Jiang, Wei
• Format: Article
• Language: English
• Subjects: actomyosin; Actomyosin - metabolism; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; AMOT; Angiomotins; Cell Differentiation; Cell Nucleus - metabolism; Cell Size; Endoderm - cytology; Endoderm - metabolism; human endoderm differentiation; Humans; Osmotic Pressure; pluripotent stem cell; Pluripotent Stem Cells - cytology; Pluripotent Stem Cells - metabolism; Signal Transduction; Transcription Factors - metabolism; YAP; YAP-Signaling Proteins - metabolism
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2024.07.001

Cell size is a crucial physical property that significantly impacts cellular physiology and function. However, the influence of cell size on stem cell specification remains largely unknown. Here, we investigated the dynamic changes in cell size during the differentiation of human pluripotent stem cells into definitive endoderm (DE). Interestingly, cell size exhibited a gradual decrease as DE differentiation progressed with higher stiffness. Furthermore, the application of hypertonic pressure or chemical to accelerate the reduction in cell size significantly and specifically enhanced DE differentiation. By functionally intervening in mechanosensitive elements, we have identified actomyosin activity as a crucial mediator of both DE differentiation and cell size reduction. Mechanistically, the reduction in cell size induces actomyosin-dependent angiomotin (AMOT) nuclear translocation, which suppresses Yes-associated protein (YAP) activity and thus facilitates DE differentiation. Together, our study has established a novel connection between cell size diminution and DE differentiation, which is mediated by AMOT nuclear translocation. Additionally, our findings suggest that the application of osmotic pressure can effectively promote human endodermal lineage differentiation. [Display omitted] •Cell size decreases during the differentiation of human pluripotent stem cells into endoderm•Hypertonic pressure is conducive to the differentiation of human definitive endoderm•Actomyosin contributes to both size diminution and endoderm promotion under hypertonic pressure•Cell size diminution represses YAP activity via promoting AMOT nuclear translocation Jiang and colleagues show that cell size exhibits a gradual decrease during human endoderm differentiation. The application of hypertonic pressure or chemical to accelerate the reduction in cell size significantly and specifically enhanced endoderm differentiation. This enhancement is reliant on actomyosin activity and achieved by promoting the nuclear translocation of AMOT, thereby repressing YAP activity.