Confined Cell Migration: The Role of Fluid Flow as a Physical Cue

Abstract

Cell motility is an essential and complex phenomenon that regulates several physiological and pathological processes in vivo, from embryonic development and tissue regeneration to disease progression. It is widely accepted that migrating cells are able to adapt to a variety of biophysical signals, including substrate stiffness, viscoelasticity, pressure, etc., that in turn can mediate the mechanism and efficiency of cell motility. This research area is of particular interest to me because migrating cells to target sites frequently encounter confinement and forces from various types of fluid flow, such as blood flow and interstitial fluid flow. The mechanosensing mechanisms by which cells sense, interpret, and respond to these physical cues from their microenvironment in vivo have yet to be fully understood. Combining engineering concepts and tools with advanced cell and molecular biology knowledge and techniques has equipped us to investigate highly active mechanisms of cell locomotion. Using PDMS-based microfluidic devices that allow fine-tuning the degree of confinement and fluid flow rates combined with live cell imaging, we were able to detect, isolate, and characterize highly migratory presenescent hMSCs based on their innate ability to move towards injured and inflammatory tissues. Migratory populations exhibit higher proliferation capacity and a lower level of DNA damage and cellular senescence. Subsequently, we were intrigued to investigate the impact of fluid forces on confined cell migration. We identified molecular mechanisms governing migratory responses observed in tightly and moderately confined microenvironments. The importance of actomyosin repolarization, intercellular calcium, ion transporters, mechanosensitive ion channels, and nuclear stiffness were demonstrated. Further research and development will hopefully generate innovative therapies, improve existing treatments, and enhance a general and fundamental understanding of cellular processes in their microenvironment, leading to profound implications for both science and medicine.