Mechanisms of epidermal stratification and force-mediated regulation of stem cell fate and positioning
As a self-renewing organ maintained by multiple distinct stem cell populations, the epidermis represents an outstanding, clinically relevant research paradigm to address mechanisms of stem cell regulation. To achieve the dynamic turnover and maintenance of the critical skin barrier function, epidermal stem cells (SC) commit to differentiate and delaminate from the basal layer to form suprabasal layers. What triggers SC differentiation, how the differentiating cells move upwards, and how differentiation and self-renewing divisions are balanced remain key open questions. Cells within the epidermis are constantly exposed to tissue- and cell-scale forces that result in changes in cell and nuclear shape and volume. Based on the emerging role of cell density and size in regulating SC fate, I hypothesize that dynamic nuclear and cell shape changes play central roles in regulating epidermal SC fate and in coupling fate changes to cell positioning within the tissue. By combining an innovative, live embryo imaging pipeline, quantitative image analysis, and theoretical models, I aim to decipher the dynamics of epidermal morphogenesis. Using transgenic reporter mice for the nucleus, plasma membrane, cytoskeleton, and differentiation, I will map large-scale and local mechanical transitions along the developmental timeline and correlate them with nuclear and cell shape changes, cell division, differentiation and delamination. I will combine these quantitative imaging experiments with computational modeling, genetic manipulation of contractility, spatial single cell transcriptomics and in vitro cell biology to discover the cellular and molecular mechanism by which tissue geometry and cell/nuclear shape guide cell fate and dynamic positioning. Altogether, this project will uncover fundamental mechanisms of epidermal stratification during development and homeostasis.