From: Max Planck Institute for Molecular Biomedicine, Münster

Will give a seminar entitled:

Tissue-scale mechanics control stem cell fate and positioning during epithelial

development

The development and maintenance of functional tissues and organs require synchronized regulation of cell state transitions and dynamic spatial positioning of specific cell states. Using the developing murine epidermis, we sought to understand the complex relationship between stem cell (SC) fate and tissue dynamics during two developmental processes: hair follicle placode development and the formation of the epidermis.

Cells generate forces through actomyosin contractility, which, along with complex interactions with tissue growth and mechanics, trigger important tissue shape changes such as folds and branches that are essential for building a functional organ. Using mouse hair follicle development as a model, we investigated how morphological transformations are coordinated with cell state transitions in space and time. We identified a key role for coordinated mechanical forces arising from the contractile, proliferative, and proteolytic activities of epithelial and mesenchymal compartments in generating epithelial invagination. Initially, after early cell fate specification, a ring of fibroblast cells gradually encircles the placode cells, generating inward contractile forces. These forces, along with polarized epithelial myosin activity, promote elongation and local tissue thickening. The resulting mechanical stresses further enhance the compartmentalization of Sox9 expression, a master transcription factor of adult hair follicles (HF), to promote stem cell positioning. Subsequently, proteolytic remodeling softens the basement membrane locally, releasing pressure within the placode. This allows for localized cell divisions, tissue fluidification, and the efficient invagination of the epithelium into the underlying mesenchyme. Our experiments and modeling reveal that dynamic cell shape transformations and tissue-scale mechanical cooperation are key factors in orchestrating organ formation.

During embryogenesis, the skin epidermis gradually transitions from a single stem cell (SC) layer to a multilayered stratified epithelium through coordinated differentiation and the upward movement of cells. However, the mechanisms that trigger initial fate commitment and how cell fate transition and positioning are coordinated during development remain poorly understood. We uncovered two mechanistically distinct phases in the formation of the stratified epidermis: (1) a rapid, growth-driven development of the first differentiated suprabasal layers, and (2) the establishment of a mechanically separated SC compartment through tissue stiffening and related cytoskeletal maturation, which subsequently requires Notch signaling-dependent early cell fate commitment to facilitate the delamination of differentiated cells across this mechanical barrier into the suprabasal layers.

Overall, our research reveals how cell state transitions and the dynamic positioning of cells are coordinated through cell- and tissue-scale mechanics during development.

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