Patient-derived extracellular matrix demonstrates role of COL3A1 in blood vessel mechanics

Doherty, E. L.; Aw, W. Y.; Warren, E. C.; Hockenberry, M.; Krohn, G.; Howell, S. D.; Diekman, B. O.; Legant, W. R.; Nia, H. T.; Hickey, A.; Polacheck, W. J.

doi:10.1101/2022.10.16.512399

bioRxiv · 10.1101/2022.10.16.512399

Patient-derived extracellular matrix demonstrates role of COL3A1 in blood vessel mechanics

Doherty, E. L.·Aw, W. Y.·Warren, E. C.·Hockenberry, M.·Krohn, G.·Howell, S. D.·Diekman, B. O.·Legant, W. R.·Nia, H. T.·Hickey, A.·Polacheck, W. J.

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Abstract

Vascular Ehlers-Danlos Syndrome (vEDS) is a rare autosomal dominant disease caused by mutations in the COL3A1 gene, which renders patients susceptible to aneurysm and arterial dissection and rupture. To determine the role of COL3A1 variants in the biochemical and biophysical properties of human arterial ECM, we developed a method for synthesizing ECM directly from vEDS donor fibroblasts. We found that the protein content of the ECM generated from vEDS donor fibroblasts differed significantly from ECM from healthy donors, including upregulation of collagen subtypes and other proteins related to ECM structural integrity. We further found that ECM generated from a donor with a glycine substitution mutation was characterized by increased glycosaminoglycan content and unique viscoelastic mechanical properties, including increased time constant for stress relaxation, resulting in a decrease in migratory speed of human aortic endothelial cells when seeded on the ECM. Collectively, these results demonstrate that causal COL3A1 mutations lead to the synthesis of ECM that differs in composition, structure, and mechanical properties from healthy donors. These results further suggest that ECM mechanical properties could serve as a prognostic indicator for patients with vEDS, and the insights provided by the approach demonstrate the broader utility of cell-derived ECM in disease modeling.

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Doherty, E. L., Aw, W. Y., Warren, E. C., Hockenberry, M., Krohn, G., Howell, S. D., Diekman, B. O., Legant, W. R., Nia, H. T., Hickey, A., Polacheck, W. J.. 2022-10-19. Patient-derived extracellular matrix demonstrates role of COL3A1 in blood vessel mechanics. https://doi.org/10.1101/2022.10.16.512399

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