"When people talk about biomechanics, they're saying that cells are able to sense and respond to changes in force," says Carman, who is also an Assistant Professor of Medicine at Harvard Medical School. "In other words, it's not only hormones and chemical signals that influence cell behaviors. Cells can actually sense physical cues and thereby modulate their function." Specifically, the new findings demonstrate that the endothelium senses an acute loss of preexisting isometric tension, and that downstream of this biomechanical signal, the ensuing recovery response generates reactive oxygen species (ROS), which are responsible for coordinating the micro-wound closure process.
Carman's previous work explored precisely how leukocytes generate vascular micro-wounds in the first place, uncovering a novel endothelial piercing activity "invasive podosomes" that are generated by the leukocytes. In this new paper, he hypothesized an equally active role for the endothelium in closing the pores and gaps made by the leukocytes.
To test this hypothesis, his laboratory set up experimental models that mimicked acute, intense inflammation. Using dynamic time-lapse and high-resolution confocal microscopy, the investigators could see the process by which leukocytes were breaching the endothelial cell. In the course of a 10-minute span, they observed that a single endothelial cell tolerated the passage of at least seven leukocytes directly through its body, and that within this brief period, the gaps closed, leaving no sign of the pores.
"The cell's restorative capacity was just so striking," says Carman. "But these early investigations were still inadequate to tell us how the breaches were being closed. We had to dig down to the sub-cellular level to understand the underlying activities and the molecular signaling mechanisms that were orchestrating these activities."
Subsequent experiments, led by co-first author Roberta Martine
|Contact: Bonnie Prescott|
Beth Israel Deaconess Medical Center