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April 2017

J Clin Invest. 2017 Apr 24. pii: 88725. doi: 10.1172/JCI88725. [Epub ahead of print]

Disruption of spatiotemporal hypoxic signaling causes congenital heart disease in mice.

Yuan X, Qi H, Li X, Wu F, Fang J, Bober E, Dobreva G, Zhou Y, Braun T.

Congenital heart disease (CHD) represents the most prevalent inborn anomaly. Only a minority of CHD cases is attributed to genetic causes, suggesting a major role of environmental or non-genetic risk factors, including diabetes mellitus, obesity, and hypoxic responses, in cardiac pathogenesis. It is known that non-physiological hypoxia during early pregnancy induces CHD, but the underlying reasons are unknown. In the heart, 2 major populations of cardiac progenitor cells defined as first heart field and the second heart field drive early cardiac morphogenesis. Progenitor cells of the first heart field generate the left ventricle and parts of the inflow tract, while the right ventricle, the atria, the outflow tract, and parts of the inflow tract are mainly derived from progenitor cells of the second heart field. The transcription factors Nkx2.5 and ISL1 play key roles in the complex network, which controls fate decisions and expansion of cardiac progenitor cells. In this study, the authors investigated the role of hypoxia for the regulation of cardiac progenitor cells and the potential crosstalk between ISL1 and Nkx2.5 in this context. They found that ISL1 positive progenitor cells in the second heart field are less hypoxic compared with the primary linear heart tube. They determined that O2 availability influences the fate of ISL1+ progenitor cells by controlling ISL1 expression and allowing thereby expansion of ISL1+ progenitor cells. Experimental induction of hypoxia responses during early heart development suppressed proliferation of ISL1+ progenitor cells and promoted precocious differentiation to cardiomyocytes. These results indicate that spatial differences in oxygenation of the developing heart serve as signals to control cardiac progenitor cell expansion and cardiac morphogenesis. The authors propose that physiological hypoxia coordinates homeostasis of cardiac progenitor cells, providing mechanistic explanations for some non-genetic causes of CHD.