Dr. Joel Boerckel

Mechanotransductive feedback control of endothelial cell motility and vascular morphogenesis

ABSTRACT:

Vascular morphogenesis requires persistent endothelial cell motility that is responsive to diverse and dynamic mechanical stimuli. Here, we interrogated the mechanotransductive feedback dynamics that govern endothelial cell motility and vascular morphogenesis. We show that the transcriptional regulators, YAP and TAZ, are activated by mechanical cues to transcriptionally limit cytoskeletal and focal adhesion maturation, forming a conserved mechanotransductive feedback loop that mediates human endothelial cell motility in vitro and zebrafish intersegmental vessel (ISV) morphogenesis in vivo. This feedback loop closes in 4 hours, achieving cytoskeletal equilibrium in 8 hours. Feedback loop inhibition arrested endothelial cell migration in vitro and ISV morphogenesis in vivo. Inhibitor washout at 3 hrs, prior to feedback loop closure, restored vessel growth, but washout at 8 hours, longer than the feedback timescale, did not, establishing lower and upper bounds for feedback kinetics in vivo. Mechanistically, YAP and TAZ induced transcriptional suppression of myosin II activity to maintain dynamic cytoskeletal equilibria. Together, these data establish the mechanoresponsive dynamics of a transcriptional feedback loop necessary for persistent endothelial cell migration and vascular morphogenesis.

NARRATIVE BIOSKETCH:

Joel received all his degrees in Mechanical Engineering, getting his Ph.D. from the Georgia Institute of Technology in 2011. His graduate work in tissue engineering led to an interest in angiogenesis and postdoctoral training in vascular biology at the Cleveland Clinic. A serendipitous failure led him to developmental biology. He started his lab at the University of Notre Dame in 2014, and was recruited to the University of Pennsylvania in 2017, where he is jointly appointed as Assistant Professor in the departments of Orthopaedic Surgery and Bioengineering. The Boerckel lab studies how mechanotransduction influences embryo development and postnatal regeneration in the skeleton and the vasculature. Joel is passionate about accelerating science dissemination and impact through preprints (e.g., bioRxiv) and building supportive scientific communities. Find him on twitter @jboerckel.