Mechano-osmotic signals control chromatin state and fate transitions in pluripotent stem cells

作者：Kaitlin P. McCreery, Aki Stubb, Rebecca Stephens, Nadezda A. Fursova, Andrew Cook, Kai Kruse, Anja Michelbach, Leah C. Biggs, Adib Keikhosravi, Sonja Nykänen, Roosa Pulkkanen, Christel Hydén‐Granskog, Jizhong Zou, Jan‐Wilm Lackmann, Carien M. Niessen, Sanna Vuoristo, Yekaterina A. Miroshnikova, Sara A. Wickström · 发表于：Nature Cell Biology · 年份：2025 · DOI：10.1038/s41556-025-01767-x · 被引用次数：24 · 研究领域：Genomics and Chromatin Dynamics、RNA Research and Splicing、Pluripotent Stem Cells Research

Acquisition of specific cell shapes and morphologies is a central component of cell fate transitions. Although signalling circuits and gene regulatory networks that regulate pluripotent stem cell differentiation have been intensely studied, how these networks are integrated in space and time with morphological changes and mechanical deformations to control state transitions remains a fundamental open question. Here we focus on two distinct models of pluripotency, preimplantation inner cell mass cells of human embryos and primed pluripotent stem cells, to discover that cell fate transitions associate with rapid, compaction-triggered changes in nuclear shape and volume. These phenotypical changes and the associated active deformation of the nuclear envelope arise from growth factor signalling-controlled changes in cytoskeletal confinement and chromatin mechanics. The resulting osmotic stress state triggers global transcriptional repression, macromolecular crowding and remodelling of nuclear condensates that prime chromatin for a cell fate transition by attenuating repression of differentiation genes. However, while this mechano-osmotic chromatin priming has the potential to accelerate fate transitions and differentiation, sustained biochemical signals are required for robust induction of specific lineages. Our findings uncover a critical mechanochemical feedback mechanism that integrates nuclear mechanics, shape and volume with biochemical signalling and chromatin state to cont...