Adipocyte-mediated electrophysiological remodeling of human stem cell - derived cardiomyocytes.

ABSTRACT

Adipocytes normally accumulate in the epicardial and pericardial layers around the human heart, but their infiltration into the myocardium can be proarrhythmic. METHODS AND RESULTS: Human adipose derived stem/stromal cells and human induced pluripotent stem cells (hiPSC) were differentiated, respectively into predominantly white fat-like adipocytes (hAdip) and ventricular cardiomyocytes (CMs). Adipocytes cultured in CM maintenance medium (CM medium) maintained their morphology, continued to express adipogenic markers, and retained clusters of intracellular lipid droplets. In contrast, hiPSC-CMs cultivated in adipogenic growth medium displayed abnormal cell morphologies and more clustering across the monolayer. Pre-plated hiPSC-CMs co-cultured in direct contact with hAdips in CM medium displayed prolonged action potential durations, increased triangulation, slowed conduction velocity, increased conduction velocity heterogeneity, and prolonged calcium transients. When hAdip-conditioned medium was added to monolayer cultures of hiPSC-CMs, results similar to those recorded with direct co-cultures were observed. Both co-culture and conditioned medium experiments resulted in increases in transcript abundance of SCN10A, CACNA1C, SLC8A1, and RYR2, with a decrease in KCNJ2. Human adipokine immunoblots revealed the presence of cytokines that were elevated in adipocyte-conditioned medium, including MCP-1, IL-6, IL-8 and CFD that could induce electrophysiological changes in cultured hiPSC-CMs. CONCLUSIONS: Co-culture of hiPSC-CMs with hAdips reveals a potentially pathogenic role of infiltrating human adipocytes on myocardial tissue. In the absence of structural changes, hAdip paracrine release alone is sufficient to cause CM electrophysiological dysfunction mirroring the co-culture conditions. These effects, mediated largely by paracrine mechanisms, could promote arrhythmias in the heart.