1. Arp2/3 complex activity enables nuclear YAP for naïve pluripotency of human embryonic stem cells
- Author
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Meyer, Nathaniel Paul, Singh, Tania, Kutys, Matthew L, Nystul, Todd G, and Barber, Diane L
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Genetics ,Regenerative Medicine ,Stem Cell Research ,Stem Cell Research - Embryonic - Human ,1.1 Normal biological development and functioning ,2.1 Biological and endogenous factors ,Humans ,Human Embryonic Stem Cells ,Actin-Related Protein 2-3 Complex ,YAP-Signaling Proteins ,Transcription Factors ,Adaptor Proteins ,Signal Transducing ,Actin Cytoskeleton ,Cell Nucleus ,Signal Transduction ,Pluripotent Stem Cells ,YAP ,actin ,cell biology ,cytoskeleton ,hippo signaling ,human ,human embryonic stem cells ,naive pluripotency ,regenerative medicine ,stem cells ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Our understanding of the transitions of human embryonic stem cells (hESCs) between distinct stages of pluripotency relies predominantly on regulation by transcriptional and epigenetic programs with limited insight on the role of established morphological changes. We report remodeling of the actin cytoskeleton of hESCs as they transition from primed to naïve pluripotency which includes assembly of a ring of contractile actin filaments encapsulating colonies of naïve hESCs. Activity of the Arp2/3 complex is required for formation of the actin ring, to establish uniform cell mechanics within naïve colonies, to promote nuclear translocation of the Hippo pathway effectors YAP and TAZ, and for effective transition to naïve pluripotency. RNA-sequencing analysis confirms that Arp2/3 complex activity regulates Hippo signaling in hESCs, and impaired naïve pluripotency with inhibited Arp2/3 complex activity is rescued by expressing a constitutively active, nuclear-localized YAP-S127A. Moreover, expression of YAP-S127A partially restores the actin filament fence with Arp2/3 complex inhibition, suggesting that actin filament remodeling is both upstream and downstream of YAP activity. These new findings on the cell biology of hESCs reveal a mechanism for cytoskeletal dynamics coordinating cell mechanics to regulate gene expression and facilitate transitions between pluripotency states.
- Published
- 2024