Abstract
The process of human cardiac development can be faithfully recapitulated in a culture dish with human pluripotent stem cells, where the impact of environmental stressors can be evaluated. The consequences of ionizing radiation exposure on human cardiac differentiation are largely unknown. In this study, human‐induced pluripotent stem cell cultures (hiPSCs) were subjected to an external beam of 3.7 MeV α‐particles at low mean absorbed doses of 0.5, 3, and 10 cGy. Subsequently, the hiPSCs were differentiated into beating cardiac myocytes (hiPSC‐CMs). Pluripotent and cardiac markers and morphology did not reveal differences between the irradiated and nonirradiated groups. While cell number was not affected during CM differentiation, cell number of differentiated CMs was severely reduced by ionizing radiation in a dose‐responsive manner. β‐adrenergic stimulation causes calcium (Ca2+) overload and oxidative stress. Although no significant increase in Ca2+ transient amplitude was observed in any group after treatment with 1 μmol/L isoproterenol, the incidence of spontaneous Ca2+ waves/releases was more frequent in hiPSC‐CMs of the irradiated groups, indicating arrhythmogenic activities at the single cell level. Increased transcript expression of mitochondrial biomarkers (LONP1, TFAM) and mtDNA‐encoded genes (MT‐CYB, MT‐RNR1) was detected upon differentiation of hiPSC‐CMs suggesting increased organelle biogenesis. Exposure of hiPSC‐CM cultures to 10 cGy significantly upregulated MT‐CYB and MT‐RNR1 expression, which may reflect an adaptive response to ionizing radiation. Our results indicate that important aspects of differentiation of hiPSCs into cardiac myocytes may be affected by low fluences of densely ionizing radiations such as α‐particles.
Highlights
The molecular series of events that lead to the development of a heart are primarily governed by developmental cues (Srivastava 2006; Chien et al 2008; Kuyumcu-Martinez and Bressan 2016)
The human-induced pluripotent stem cell cultures (hiPSCs) were originally obtained from human cardiac fibroblasts (Zhang et al 2015)
From day 7 and onward of cardiomyocyte differentiation (CD), the medium contained insulin according to the GiWi protocol and was changed every other day before the cells started beating, after which the medium was changed daily once the hiPSC-CMs started beating
Summary
The molecular series of events that lead to the development of a heart are primarily governed by developmental cues (Srivastava 2006; Chien et al 2008; Kuyumcu-Martinez and Bressan 2016). Humans are constantly exposed to low-level ionizing radiation from natural sources. Normal tissue may be exposed to low doses/low fluences of radiation during the course of occupational activities or radiotherapy (Azzam et al 2003, 2016). Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.
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