Kalender

Embryonic development is coordinated in space and time despite the inherent variability in gene expression, cell dynamics and tissue morphogenesis. Mouse embryos can adjust their size variabilities during development. However, the mechanisms by which cells sense and correct embryo size differences remain elusive. We measure embryo growth dynamics in utero and ex vivo and present a framework for studying tissue growth control.

Complex organ function arises from spatially coordinated cell identities. Liver function depends on segregated metabolic programs along the porto-central axis. How this spatial logic and multicellular dynamics are disrupted in human chronic liver disease (CLD) remains unknown. By combining complex lineage tracing in mice and multimodal spatial transcriptomics in patients, we show that CLD across diverse etiologies is defined by a global collapse of metabolic zonation. Using spatial neighborhood analyses, we develop an entropy-based framework that quantitatively captures disruption of metabolic order and multicellular dynamics across three CLD etiologies. Mechanistically, impaired zonated WNT/β-catenin signaling drives loss of pericentral metabolism, whereas ectopic enrichment of WNT/RSPO ligands within injury niches induces transient metabolic reprogramming and hepatocyte plasticity during regeneration. YAP signaling promotes hepatocyte proliferation and induces biliary metaplasia in periportal hepatocytes, but therapeutic targeting of the pathway fails to restore liver regeneration following extended hepatectomy. Together, these findings demonstrate that hepatocyte identity and zonation are fundamentally fluid. Restoring functional tissue in chronic liver failure requires looking beyond static cell populations to target the underlying spatial signaling architectures that constrain aberrant plasticity and license productive organ regeneration.

Research in our lab focuses on understanding how cells in the early embryo integrate genetic and epigenetic information to initiate and orchestrate a new developmental programme. After fertilisation of the oocyte by the sperm, the resulting zygote acquires the unique capacity to form a complete new organism. This is a universal principle across species and is fundamental for the preservation of species and for multicellularity. At these early developmental stages, genetic, epigenetic and mechanical mechanisms are in place. Yet, how these regulatory layers are integrated at the molecular level remains still a poorly understood, yet exciting area of research. I will present our work investigating how the pervasive presence of transposable elements in mammalian genomes, chromatin function, and genome nuclear organisation are integrated with nuclear mechanics to shape and regulate early developmental programmes. I will also illustrate how we leverage these findings to restore cellular plasticity for reprogramming cell fates.

The mechanical stiffness of the nucleus regulates its deformation under force, making it an emerging central mechanosensor of the cell, which interacts with numerous signaling macromolecules and pathways. In particular, Yes-Associated Protein (YAP), is a key transcription factor in diverse physiology and disease whose activity is in part regulated by nuclear compression. This makes downstream activity of YAP in diverse contexts directly regulated by the forces applied to the nucleus, as well as the nucleus’s mechanical properties. Previous studies have related nuclear mechanics with YAP activity, but we still lack an understanding of what nuclear deformation specifically regulates YAP, and its relationship with mechanical stimuli. In this talk I will discuss some of our ongoing work and recent findings related to YAP mechanosensing in the nucleus. Our lab has shown that nuclear compression from diverse sources of substrate stiffness mediated contractile force to external osmotic pressure reveal an identical scaling of YAP activity as a function of nuclear volume. I will discuss how examining the details of nuclear deformation in mesenchymal stem cells (MSCs), we find that specifically nuclear curvature is a clear predictor for YAP mechanosensing in the nucleus. By controlling the nuclear curvature, we are able to precisely direct the differentiation lineage of MSCs in culture, with numerous potential therapeutic applications. Beyond differentiation, we have also revealed how nuclear deformation mediated YAP activity regulates cellular senescence. Examining Hutchinson Gilford Progeria Syndrome (HGPS) cells with healthy wild type fibroblasts, we find that HGPS nuclei are stiffer and wrinkled due to the nucleoplasmic spoke-like structure of lamin A/C in HGPS nuclei. We find that increased nuclear stiffness is correlated with reduced YAP activity, which in turn promotes cellular aging as assessed by biomarkers. Directly mechanically compressing stiff cells lead to a dramatic increase in YAP activity and a reduction in cellular aging. These studies of nuclear mechanics reveal its role in YAP mechanotransduction with broad impact across diverse cell functions and pathology.

TBA