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Cardiovascular Engineering

Lymphatic engineering in Cardiovascular Diseases and Regeneration

Designing Synthetic Matrix for Lymphatic Regeneration

Friday, October 25, 2024
5:00 PM - 5:30 PM EST
Location: Room 328

Introduction:  Controlling the formation of new lymphatic vessels has been postulated as an innovative therapeutic strategy for various disease phenotypes, including neurodegenerative diseases, metabolic syndrome, cardiovascular disease, and lymphedema. Yet, compared to the blood vascular system, little is known about the molecular regulation that controls lymphatic tube formation in a synthetic matrix.

Materials and

Methods:  Here, we utilize hyaluronic acid (HA)-hydrogels to design a novel platform for decoupled investigation into how mechanical and biochemical cues regulate lymphatic vessel formation in a synthetic matrix. Using HA and controlling the degree of modification provides a method to preserve and modulate key lymphatic markers Prox1, LYVE-1, and Pdpn. The chemistry of the system allows for spatial and temporal patterning of specific peptides and substrate stiffnesses, and an MMP-sensitive crosslinker allowed cells to degrade and remodel their matrix.

Results, Conclusions, and Discussions: Through systematic optimization of multiple parameters, we have designed a system that allows human lymphatic endothelial cells (LECs) to self-assemble into vessels in vitro within 3 days. These engineered vessels can be cultured for up to 3 weeks and can be used for high-throughput mechanistic studies, or can be implanted into immunodeficient mice where they have demonstrated the ability to integrate and mature. Collectively, these studies report a novel, fully-defined 3D synthetic matrix system capable of generating lymphatic vessels in vitro that provide promise as an in vitro screening platform and as a therapeutic vessel transplant, which to our knowledge, is the first ever 3D lymphatic tissue engineering approach to not require the use of support cells.

Acknowledgements (Optional):  We acknowledge support from the University of Notre Dame through “Advancing Our Vision” Initiative in Stem Cell Research, Harper Cancer Research Institute – American Cancer Society Institutional Research Grant (IRG-17-182-04), American Heart Association through Career Development Award (19-CDA-34630012 to D.H.-P.), National Science Foundation (2047903 to D.H-P.), and National Institutes of Health (1R35-GM-143055-01 to D.H.-P.).