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

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 vEDS patient-derived fibroblasts harboring COL3A1 mutations synthesize 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. STATEMENT OF SIGNIFICANCE: The role of collagen III ECM mechanics remains unclear, despite reported roles in diseases including fibrosis and cancer. Here, we generate fibrous, collagen-rich ECM from primary donor cells from patients with vascular Ehlers-Danlos syndrome (vEDS), a disease caused by mutations in the gene that encodes collagen III. We observe that ECM grown from vEDS patients is characterized by unique mechanical signatures, including altered viscoelastic properties. By quantifying the structural, biochemical, and mechanical properties of patient-derived ECM, we identify potential drug targets for vEDS, while defining a role for collagen III in ECM mechanics more broadly. Furthermore, the structure/function relationships of collagen III in ECM assembly and mechanics will inform the design of substrates for tissue engineering and regenerative medicine.

• Authors: Elizabeth L Doherty, Wen Yih Aw, Emily C Warren, Max Hockenberry, Chloe P Whitworth, Grace Krohn, Stefanie Howell, Brian O Diekman, Wesley R Legant, Hadi Tavakoli Nia, Anthony J Hickey, William J Polacheck
• Journal: Acta biomaterialia (Acta Biomater) Vol. 166 Pg. 346-359 (08 2023) ISSN: 1878-7568 [Electronic] England
• PMID: 37187299 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Chemical References

• Collagen Type III
• COL3A1 protein, human

Topics

• Humans
• Endothelial Cells (metabolism)
• Ehlers-Danlos Syndrome (genetics, metabolism)
• Mutation, Missense
• Mutation (genetics)
• Ehlers-Danlos Syndrome, Type IV
• Extracellular Matrix (metabolism)
• Collagen Type III (genetics, chemistry)