Studying the cellular ecology of organ formation using a novel tissue reconstitution system - Abstract:
Our organs function via repetitive morphological structures like follicles, vertebra, and villi that rival the
orderliness achieved by modern manufacturing. In recent decades, the generation of these periodic structures
has been primarily ascribed to pre-existing gene expression patterns. In the developing skin, however, recent
studies suggest that the concept of a molecular blueprint be shed in order to consider mechanisms where cells
self-organize through physical interactions. Self-organization mechanisms are especially uncharted in the
collectives of fibroblasts that make up mesenchymal tissues. In our latest work, we find that the self-
organization of fibroblasts embedded in extracellular matrix (ECM) is sufficient to robustly generate the ordered
structures of the skin: a grid of pre-follicle aggregates. These results highlight the pattern-generating power of
the mesenchyme, where the formation of cell-ECM supra-structures may prove to be a broadly-used tool to
efficiently and robustly initiate ordered tissue structures. A central gap that remains is dissecting how the
biophysical features of individual cells impact the dynamics of cell-cell coordination to enable the structuring of
organs. In our proposed studies of such cellular ecology, we aim to understand how cells convert energy
injected at the molecular scale to couple motion, organize force, and communicate during tissue
morphogenesis. This inquiry is made possible by a novel collective cell behavioral platform that successfully
captures the self-organizing process that skin progenitors undergo as they coalesce into an ordered and
structurally linked tissue. We will investigate how biophysical features impact self-organization and the cell-cell
linkages that emerge as a result. Based on our recent findings, we propose to investigate bioelectrical
signaling to determine whether calcium oscillatory behavior can serve as a means to make mechanical
coupling of cells more robust. We will also probe the energetic flows occurring across the cell collective as they
self-organize in order to discover which metabolic pathways serve to guide the energy flows required for cells
to express their mechanical behavior. Understanding how physical entities such as mechanics, electricity, and
energy are co-regulated during mesenchymal tissue self-organization formation will offer new pathways for
tissue design and reconstitution as well as present new avenues for drug development.
