Yarelis Gonzalez-Vargas
BME PhD Proposal Presentation

Date:2022-06-16
Time: 10:00 am - 12:00 pm
Location / Meeting Link: Suddath Seminar Room (IBB 1128) / https://gatech.zoom.us/j/95881427015

Committee Members:
J. Brandon Dixon, PhD (Advisor) Jennifer M. Spangle, PhD Rudolph L. Gleason, PhD Andrés J. García, PhD C. Matthew Hawkins, MD


Title: Bioengineered 3D in vitro strategies to investigate phenotypic and genotypic differences in lymphatic network sprouting

Abstract:
Millions of people are affected by debilitating conditions related to the lymphatic system , which is responsible for maintaining homeostasis and immune cell transport, but the mechanisms that govern the formation of lymphatic vessels (LVs) are still understudied. Lymphatic dysfunction can be characterized by the hyperactivation or hypoactivation of lymphangiogenesis, the process by which new lymphatics are formed. Post-developmentally, LVs are thought to arise from pre-existing vasculature such as collecting LVs (CLVs). These vessels differ from lymphatic capillaries in that they have a surrounding layer of lymphatic muscle cells (LMCs) generating the contraction that transports lymph, around the luminal layer of lymphatic endothelial cells (LECs). LMCs are considered to have a role in promoting lymphangiogenesis. Although, studies have been able to identify mediators of lymphatic capillary lymphangiogenesis, there are no in vitro platforms, apart from CLV explant studies, to investigate the role of muscle cells and sprouting of the lymphatic network from the CLV. Further, there is an unmet clinical need to define the molecular mechanisms of post-natal lymphangiogenesis and drivers of dysregulated growth and to utilize biomaterials strategies that aid in the regeneration of lymphatics. Lymphatic malformations (LMs) are a form of rare (1:4000 live births) vascular anomalies that result from somatic mutations, and which are usually apparent after birth. The heterogeneity of this disease has challenged our knowledge of the molecular underpinnings that drive LMs and has hindered the development of a standard care of treatment for these patients. To this end, I present a bioengineered platform that incorporates the major components of the CLV; LECs and LMCs and a basement membrane coating around LECs to support assembly of lymphatic networks. Next, I introduce a reverse engineering approach to model the dysregulated growth that occurs in LMs, using patient-derived biopsies. This research proposes to use an established poly (ethylene glycol) (PEG)-based hydrogel platform to 1) recapitulate CLV network sprouting using primary lymphatic cells in a 3D spheroid, 2) reverse engineer LMs from patient vascular anomaly biopsies, and 3) to elucidate the phenotypic and genotypic effects of matrix stiffness on sprouting lymphangiogenesis.