Human blood–vessel–on–a–chip reveals new cell migration–based mechanism for fibrotic diseases.
All of the blood in the human body circulates within its vast network of arteries, veins, and capillaries, separated from organs and tissues by an inner layer of endothelial cells and an outer layer of vessel–supporting mural cells and extracellular matrix that very selectively regulate what can diffuse in and out. When the endothelial cell barrier is disrupted, as in the case of injury and disease, blood leaks out of the vasculature and triggers inflammation and clotting, which can cause acute organ failure, tissue damage, and other problems.

A team of scientists at the Wyss Institute at Harvard University and Boston University has created a 3D blood–vessel–on–a–chip model to investigate endothelial barrier failure, and found that inflammation disrupts the connections between endothelial cells and mural cells, causing the mural cells to retract or even detach from their usual position surrounding blood vessels and leading to further leakage.

“Most of the studies out there have thought that these different cell types communicate via the diffusion of growth factor molecules, but we’ve found that the physical connections, or junctions, between them are just as important for proper barrier function,” says co–first author Stella Alimperti, PhD, a Postdoctoral Researcher at the Wyss Institute and Boston University.

The research was published in the journal PNAS. The blood–vessel–on–a–chip consists of a 3D matrix made of collagen through which passes a hollow tube that is seeded with endothelial cells on the inner surface and primary human bone marrow stromal cells (hBMSCs), a type of mural cell, on the outer surface. The researchers then perfused known barrier–disrupting molecules into the vessel–mimicking tube to evaluate how the cells respond: lipopolysaccharides (LPS; a toxin produced by some types of bacteria), thrombin (THBN), and tumor necrosis factor alpha (TNFalpha). After one hour of treatment, they observed a dramatic increase in the permeability of the endothelial barrier and, interestingly, that the mural cells either retracted or detached from the vessels altogether. These results were confirmed by similar observations of openings forming in skin blood vessels in vivo following exposure to LPS.

Once mural cells detach from blood vessels they can migrate to other chronically injured parts of the body and contribute to fibrosis, or the accumulation of excess connective tissue that disrupts normal healing and organ function, which is implicated in a slew of diseases from cystic fibrosis to Crohn’s disease to liver cirrhosis.

“Our study suggests that inflammatory molecules, not cell signaling proteins, are what drive mural cells into the bloodstream, and that the interaction between mural cells and endothelial cells plays a much larger role in fibrosis than previously thought,” says Chris Chen, MD, PhD, Associate Faculty Member at the Wyss Institute and Founding Director of the Biological Design Center and Distinguished Professor of Biomedical Engineering at Boston University, who is the corresponding author of the paper.