CAREER: Modeling the role of blood and lymphatic vessels in adipose tissue

In the past twenty years, our understanding of adipose (fat) tissue has been transformed. We now realize that adipose tissue is a complex endocrine (hormone producing) organ capable of regulating whole body homeostasis, i.e., provide the stability and constancy needed to function properly. Obese adipocytes (fat cells) expand from three to six times their original volume, while blood vessels do not grow with the expanded tissue.

Lymphatic vessels, whose main function is to return tissue fluids (primarily lymph) back to the blood, are thought to have an increased role in supporting the tissue; however, no laboratory model exists to study these interactions outside of a body. To address the need for such models, this CAREER project seeks to build a biomimetic (biology mimicking) model of vascularized adipose tissue with a lymphatic component that will be used to explore the impact of transport between blood, lymph, and adipose tissue on the development of obesity.

The educational objectives of this project are to (1) initiate a science communication workshop to help trainees improve communication skill sets and to educate others on the racial and healthcare disparities associated with obesity; and (2) develop a gallery of failed experiments to provide an informal setting to help trainees change the narrative from perceived failure to an opportunity to explain interesting findings.

The investigator’s underlying research goal is to change the current approach to adipocyte and adipose tissue (AT) research in three different ways: (1) move from 2D studies in culture models to functional 3D in vitro models with human cells, (2) move away from the “adipo(cyte)-centric” view of AT that does not account for the tissue complexity in vascularization, matrix, among other factors, and (3) move from static models to models that acknowledge that tissue is constantly expanding and breaking down to account for changing adipocyte volumes. Towards this goal, this CAREER project aims to build a biomimetic, vascularized "fat-on-a-chip" model to explore the impact of transport between blood, lymph, and AT on development of obesity using human-derived cells.

This model will answer the overarching scientific question of how lymphatic remodeling and function are altered in an obese adipose tissue microenvironment by enabling quantification of both adipocyte and lymphatic vascular function from two important angles: (1) functional, which includes metabolic outcomes and barrier function under flow and (2) structural, which includes matrix and vascular remodeling. Since the system is amenable to gene/protein expression assays, confocal microscopy and soluble factor sampling, the project is also expected to reveal mechanistic insights.

The Research Plan is organized under three objectives: (1) Develop, characterize, and validate a microphysiological model of AT with lymphatics, benchmarking to human AT samples while evaluating the effect of static versus flow conditions on vessel barrier function, cell-cell junctions, and fluid accumulation; (2) Develop an obese model of AT containing lymphatic vessels to assess the impact of obese cues on lymphatic remodeling and lymphangiogenesis, which will be accomplished by exposing the model to hypoxia (1% O2) using primary adipocytes and endothelial cells from healthy and obese subjects; and (3) Explore the role of the matrix properties on lymphatic remodeling and function. In summary, this reductionist in vitro model of adipose tissue will provide a foundational platform for vascular research, obesity research and therapeutic testing.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.