Development of a novel hiPSCs-derived Vascularized-Epicardial-Adipose-Tissue-on-Chip model to investigate cellular crosstalk in healthy and stressed states

Obesity-associated metabolic and cardiovascular diseases (CVDs) are serious public health concerns.

A fat depot surrounding the heart, known as epicardial adipose tissue (EAT), is likely contributing to the pathologic conditions leading to CVDs.

But it might also play a protective role during ischaemic events highlighting a complex role of EAT in heart homeostasis and disease.

Some studies report post-menopausal women having an increased EAT suggesting that changes in levels of of sex hormones affect EAT and may cause sex-specific contributions to metabolic diseases. Though EAT covers nearly 80% of a human heart, it is virtually absent in rodents.

Given the underexplored role of EAT in the pathology of CVDs, and the lack of animal models, human in vitro cardiovascular EAT model is necessary.

VEAT-chip proposes to develop the first human induced pluripotent stem cells (hiPSCs) derived, fully autologous, vascularized EAT-on-chip model. The project will start with establishing a novel protocol to obtain epicardial adipocytes.

Then, those cells will be integrated into hiPSCs derived cardiac-specific vessels-on-chip to generate a vascularized EAT-on-chip.

Given an undetermined role of sex hormones for EAT function and an unclear balance of protective and toxic effects of EAT in pathological settings, vEAT-chip will explore hormone- induced changes in function of EAT during homeostasis and stressed conditions.

In a final aim of the project, addition of cardiomyocytes (CMs) to the system will result in a model resembling a portion of the heart wall.

By combining novel hiPSCs differentiation protocols, organ-on-a-chip technologies, advanced microscopy techniques, and global transcriptome and secretome analysis, the VEAT-chip project will reveal EAT-associated factors affecting healthy function of cardiac-specific vessels and CMs.

Ultimately, VEAT-chip will provide a novel means to study cellular crosstalk and unravel mechanisms associated with cardiometabolic diseases.