The role of the epicardium and IRE1 in mediating environmental exposure on cardiac function

Advances in cell culture techniques and stem cell technology have enabled generation of 3-
dimensional organoids capable of recapitulating the structure and physiology of human organs
better than 2D cultures. These organoids can aid in identifying early biomarkers of diseases, and
understanding the impact of environmental factors on the initiation and progression of diseases.
We recently used our human heart organoids (hHOs) derived from human induced pluripotent
stem cells (iPSCs) to explore changes in lipid profile mediated by endoplasmic reticulum (ER)
stress sensor proteins.
Exogenous chemicals (e.g., per-and polyfluoroalkyl substances (PFAS), drugs, etc.) and
endogenous metabolites (e.g., cholesterol and saturated fatty acids (SFAs)) negatively affect
cardiac function. PFAS are found in many household cleaning products and commercial
packaging materials. Once released to the environment, these “forever chemicals” degrade
slowly, resulting in detectable levels in drinking water, food, and animals, including humans. PFAS
are ubiquitous environmental contaminants that also accumulate in the food chain, which is one
of the main routes of human exposure. Evidence have linked PFAS to altered lipid profile and
cardiovascular disease (CVD). We and others have found that PFAS induces ER stress, notably
inositol-requiring enzyme 1α (IRE1α) signaling. ER stress and activation of IRE1α is involved in
various conditions that advance heart diseases. Thus far, studies on the changes in lipid
composition induced by PFAS has been limited to cholesterol, lipoproteins and TG. We found that
(i) IRE1α mediates changes in the lipid profile (notably, long-chain fatty acids) in our hHOs, and
(ii) PFAS activates IRE1α signaling and is linked to dyslipidemia and CVD risk. Therefore, we
hypothesize that PFAS activation of IRE1α signaling alters the lipid profiles and negatively affects
cardiac function. We further propose that our organoids, which contain epicardial cells (that
provide trophic factors and can mediate lipid metabolism) in addition to cardiomyocytes, enable
investigation of the influence of epicardial cells on the cardiac lipid profile and function. In the first
aim, we will investigate the changes in lipid content (i.e., very long chain long chain fatty acids:
odd and even) and cardiac function induced by PFAS exposure and mediated by IRE1α. In the
second aim, we will investigate the PFAS-induced changes in lipid profile and cardiac function
mediated by the epicardium.

Grant Number: 1R21ES037451-01
NIH Institute/Center: NIH
Principal Investigator: CHRISTINA CHAN