Geometrical Regulation of Collective Cellular Responses in Three-Dimensional Space and Time - The self-organization and spatial patterning of cells are critical for tissue morphogenesis and regeneration. While biochemical factors have traditionally been the focus of developmental and regenerative biology research, emerging studies suggest that tissue geometry plays a pivotal role in controlling cellular behavior and tissue function. Our research program investigates how macroscopic 3D tissue geometries—such as curvature, concavity, continuity, and aspect ratio (length-to-width ratio)—independently influence cell morphology, gene expression, and tissue homeostasis. The program will initially focus on human mesenchymal cells in skin and vascular tissues, addressing three fundamental questions: (1) How does tissue geometry influence steady-state cell morphology and transcriptional activity? (2) How do cells respond to dynamic changes in tissue geometry? (3) How are cellular signals propagated within tissue in response to changing geometric boundaries? To systematically decouple and investigate the effects of specific geometric cues in 3D, we will leverage our recently developed Edgeless Tissue Constructs (ETC)—a cutting-edge platform that allows precise control over tissue continuity, curvature, and concavity. Using this platform, we will examine cellular alignment, extracellular matrix organization, proliferation, migration, and shifts in transcriptional signatures in response to individual geometric cues under steady-state conditions. Additionally, we will integrate the ETC with robotic and automated systems to investigate how these dynamic 3D geometries—such as disrupted continuity (e.g., wounds) or increased curvature (e.g., aortic aneurysm)—affect cells independently of other microenvironmental factors like inflammation or parenchymal signals. Finally, we aim to uncover the biomolecular and biomechanical pathways by which cells sense new geometric boundary conditions—such as discontinuous boundaries—and propagate signals throughout the tissue. To achieve these goals, we will employ a comprehensive array of technologies, including single-cell and spatial transcriptomics (e.g., Xenium), computational modeling, mechanical testing (e.g., nanoindentation), confocal imaging (e.g., second-harmonic generation), and gene-editing tools. After establishing a strong foundation with human mesenchymal cells in the first five years, the program will expand to include other human cell types (e.g., epidermal, endothelial, and immune cells) and tissue types (e.g., uterus, adipose). Ultimately, this research may lead to the discovery of novel therapeutic strategies that target tissue geometry, as well as the development of more physiologically relevant organ models and grafts guided by geometric cues. Moreover, this interdisciplinary program will provide exceptional training opportunities for scientists, engineers, and clinicians at various educational levels by leveraging my established collaborations at Columbia University.
