Cardiac calcium regulation in human induced pluripotent stem cell cardiomyocytes: Implications for disease modeling and maturation

FIGURE 1. Differences in calcium regulation between adult human cardiomyocytes and in hiPSC-derived cardiomyocytes. In adult human cardiomyocytes (left), T-tubules result in close proximity between L-type Ca2+ channels and RyR2 allowing for a larger release of Ca2+ from the SR, quickly diffusing into the cytosol and going to the myofilaments to facilitate contraction as well as into closely tethered mitochondria to stimulate ATP production. Ca2+ is then primarily sequestered back into the SR via SERCA. In hiPSC-CMs (right), increased distance between L-type calcium channels and RyR2 results in less Ca2+ release from the SR, requiring the cells to rely more heavily on L-type Ca2+ influx to facilitate contraction. After relaxation a larger fraction of the cytosolic Ca2+ is removed via the Na+/Ca2+ exchanger.

FIGURE 2. Human induced pluripotent stem cell cardiomyocytes are immature but reflect human heart development. Insights from cardiac morphogenesis has facilitated differentiation of hiPSC to hiPSC-CMs. Currently, hiPSC-CMs are immature compared to adult human cardiomyocytes, but further strategies for maturation may advance the maturity of hiPSC-CMs towards an adult phenotype.

FIGURE 3. Maturation of calcium signaling in hiPSC-CMs over time in comparison to adult human cardiomyocytes. Early hiPSC-CMs (left) lack the structural organization of adult CMs (right), an immaturity reflected in their respective Ca2+ transients. Ca2+ transients of immature hiPSC-CMs exhibit a smaller amplitude as well as much slower rise times and recovery rates. Maturation of the hiPSC-CMs (middle) results in increased structural organization of the cells and Ca2+ transients with larger amplitudes and faster rise times and recovery rates. Strategies to mature Ca2+ handling in hiPSC-CMs will be critical to achieve more adult human like Ca2+ transients.