Plakoglobin is a mechanoresponsive regulator of naive pluripotency.
Biomechanical cues are instrumental in guiding embryonic development and cell differentiation. Understanding how these physical stimuli translate into transcriptional programs will provide insight into mechanisms underlying mammalian pre-implantation development. Here, we explore this type of regulation by exerting microenvironmental control over mouse embryonic stem cells. Microfluidic encapsulation of mouse embryonic stem cells in agarose microgels stabilizes the naive pluripotency network and specifically induces expression of Plakoglobin (Jup), a vertebrate homolog of β-catenin. Overexpression of Plakoglobin is sufficient to fully re-establish the naive pluripotency gene regulatory network under metastable pluripotency conditions, as confirmed by single-cell transcriptome profiling. Finally, we find that, in the epiblast, Plakoglobin was exclusively expressed at the blastocyst stage in human and mouse embryos - further strengthening the link between Plakoglobin and naive pluripotency in vivo. Our work reveals Plakoglobin as a mechanosensitive regulator of naive pluripotency and provides a paradigm to interrogate the effects of volumetric confinement on cell-fate transitions.
Acknowledgements: T.N.K. and M.H. received scholarship support from AstraZeneca, J.D.J. from the BBSRC, A.L.E. from the Cambridge Trusts and the EU H2020 Marie Curie ITN MMBio and Ka.F. from the MRC and St. John’s College Cambridge. This work was supported by the Wellcome Trust (WT108438/C/15/Z and WT RG89228). F.H. is an H2020 ERC Advanced Investigator (695669), T.E.B. is a Wellcome Trust and Royal Society Sir Henry Dale Fellow. We are grateful to Dr. Geraldine M. Jowett for critical reading and constructive comments on the manuscript. We further thank Alisa Maring regarding her expertise in Western blotting. Finally, we thank Joana Cerveira the Flow Cytometry Facility Manager of the School of the Biological Sciences at the University of Cambridge.
Wellcome Trust (108438/E/15/Z)
Biotechnology and Biological Sciences Research Council (1795140)
European Commission Horizon 2020 (H2020) ERC (695664)
European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (721613)