Congenital heart disease (CHD) is the most common cause of congenital anomaly and a leading cause of morbidity and mortality worldwide. Generation of cardiomyoctyes derived from pluripotent stem cells (PSCs) has opened new avenues for investigation of human cardiac development. Here we report that uric acid (UA), a physiologically abundant compound during embryonic development, can consistently and robustly enhance cardiac differentiation of human PSCs including hESCs and hiPSCs, in replacement of ascorbic acid (AA). We optimized treatment conditions and demonstrate that differentiation day 0–2, a period for specification of mesoderm cells, was a critical time for UA effects. This was further confirmed by UA-induced upregulation of mesodermal markers. Furthermore, we show that the developing mesoderm may be by directly promoted by SNAI pathway-mediated epithelial–mesenchymal transition (EMT) at 0–24 h and a lengthened G0/G1 phase by increasing the ubiquitination degradation in 24–48 h. These findings demonstrate that UA plays a critical role in mesoderm differentiation, and its level might be a useful indicator for CHD in early fetal ultrasound screening.
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This work was supported by the National Natural Science Foundation of China (81570215 and 81100142), The Cultivating Project Grants of Beijing for Highly Talented Men of Medicine (2014-3-042), Beijing Key Laboratory of Cardiovascular Diseases Related to Metabolic Disturbance (3500-11722812), and Basic-clinical Research Program of Capital Medical University (17JL15).
Conflict of interest
The authors declare that they have no conflict of interest.
Edited by R. De Maria