University of Pittsburgh Department of Biological Sciences Presents:
Monday Fall 2017 Seminar Series
Dr. Lance Davidson
University of Pittsburgh Swanson School of Engineering
Russell Lecture
"All stressed out: physical tension drives mesenchymal- to- epithelial transitions during development"
Monday, September 25, 2017
169 Crawford
10:50 Refreshments
11:00 Seminar
Abstract: Cells and tissues in the early embryo assemble through the action of both mechanical forces and chemical signals to produce the basic body plan and establish functional organs. Our research explores the principles of tissue self-assembly during embryonic morphogenesis while our applied research projects seek to use those principles to direct self-assembly in engineered tissues. In this seminar I will present recent efforts that exposed how proper heart formation involves coordinated mechanical action by endoderm and mesenchymal heart progenitor cells (HPCs). Bilateral populations of HPCs begin their movement to the ventral midline as mesenchymal cells but transition to epithelial before they form the ventral heart trough. To understand the role of mechanics in the spatial and temporal control of this mesenchymal-to-epithelial transition (MET) we carried out a biomechanical analysis of the heart forming region (HFR). Time-lapse imaging of the HFR reveals a complex pattern of shape change, first contracting in the anterior-posterior direction then elongating. Strain maps from this analysis combined with biomechanical measurements of tissue compliance with microaspiration reveal MET coincides with peak levels of tissue stress in the HFR suggesting mechanical cues from the microenvironment are responsible for inducing MET in the HPCs. To test such a role for tissue stress we took three different approaches to modulating mechanics: 1) overexpression of constitutive active Rho-GEF, 2) incubation with activators and inhibitors of cell contractility, and 3) exogenously applied strain. Overexpression of contractility by targeted mRNA injections revealed that MET could be driven non-cell autonomously by stiffening endoderm. Transient disruptions in MET with small molecule inhibitors and activators of contractility revealed decreased contractility could inhibit while increased contractility could precociously induce MET. Finally, using only physical means to strain the HFR we were also able to induce early MET. Each of these three perturbations of the mechanical microenvironment resulted in specific defects in the architecture of the larval heart which manifest in defects in cardiac output. Thus, using biophysical and cell biological methods we identified endogenous changes in the mechanical microenvironment in the heart forming region (HFR) that appear to drive HPCs into a mesenchymal-to-epithelial transition (MET) and how lesions in that regulation impact heart structure and function.