Our long-term objective is to study the organizing principles that establish complex skin architectures required for optimal skin functions. We have been using developing skin as experimental models because of their distinct patterns which we use as a readout and their accessibility to experimentation. In the past, we have taken an analytical approach to study the disruption of tissue patterns by altering expression levels of different diffusible morphogens. Recent work from us and others have enlightened us that biophysical processes also play integral roles in tissue patterning, and these roles have been under appreciated. We now explore the ramifications of this novel understanding. Here we formulate a general hypothesis that tissue patterning occurs by integrating molecular signaling and biophysical events. Newly expressed molecules on cells lead to changes in the physical properties of cells and their surrounding matrix, causing disequilibrium that drives biophysical processes to the next stage. Mechano-chemical coupling leads to new molecular expression and so on, leading to the building of complex architectures. We will evaluate three key morphogenetic events. First, the periodic patterning process that converts the skin from one morphogenetic field to multiple skin appendage units. We suggest there are multi-layered controls. Tissue mechanics may facilitate Turing patterning and help the propagation of the bud forming wave, while gap junctions may alter the diffusion of intra-cellular second messengers to modulate the results of Turing patterns. Second, the formation of stem cell-based skin appendage follicles in each unit. The margin of the feather bud shows planar cell polarity, Tenascin C, and MMP14-FRET activity that drives bud margin epithelium to invaginate into the dermis. Fate maps of stem cells and dermal papillae will be generated using singe cell RNA sequencing and lineage tracing, and the results will be compared with that of hair follicles for key similarities. Third, adaptive patterning in which adnexal structures such as blood vessels, nerves, dermal muscles, etc. are integrated back to the skin to form one functional unit. We will use the assembly of the dermal muscle network as a paradigm to explore these principles. The competence, specification and plasticity of dermal cell fates during this process will be analyzed epigenetically using a SMA mechanosensor in living explants. By exploring the roles of tissue mechanics in during tissue patterning of the skin, we can obtain a more holistic understanding of the self- organizing processes in the development and regeneration of the skin. This knowledge will have significant applications toward regenerative medicine in the future.
Tissue patterning is a fundamental process that establishes complex skin architectures required for optimal skin functions. We have used the developing skin as experimental models to study the morphogenetic processes involved in the generation of multiple appendage units, the formation of cyclic renewable follicles, and the assembly of the muscle network. The newly learned principles and concepts will enhance our ability to promote tissue patterning in engineered skin and to move forward toward applications in future regenerative medicine.
