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Published on: May 10, 2020
Uric acid: a potent molecular contributor to pluripotent stem cell cardiac differentiation via mesoderm specification
Bingbing Ke1, Yujie Zeng1, Zhihong Zhao2
1Department of Emergency Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China.
Insights
Uric acid (UA) enhances cardiac differentiation of human pluripotent stem cells (PSCs) by promoting mesoderm development. This finding suggests UA may serve as an early indicator for congenital heart disease (CHD).
Area of Science:
- Developmental Biology
- Stem Cell Biology
- Cardiovascular Research
Background:
- Congenital heart disease (CHD) is a significant global health concern, driving research into human cardiac development.
- Pluripotent stem cells (PSCs) offer a powerful model for studying cardiac development and disease.
- Ascorbic acid (AA) is commonly used to promote cardiac differentiation, but alternative enhancers are sought.
Purpose of the Study:
- To investigate the role of uric acid (UA) in enhancing cardiac differentiation of human PSCs.
- To identify the critical timing and mechanisms by which UA influences cardiac development.
- To explore the potential of UA as a biomarker for congenital heart disease.
Main Methods:
- Human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) were differentiated into cardiomyocytes.
- Uric acid (UA) was used as a substitute for ascorbic acid (AA) to assess its effect on cardiac differentiation.
- Gene expression analysis was performed to evaluate mesodermal markers and signaling pathways (e.g., SNAI, EMT).
Main Results:
- Uric acid (UA) robustly enhanced cardiac differentiation of human PSCs (hESCs and hiPSCs).
- The critical window for UA's effect was identified as differentiation days 0-2, coinciding with mesoderm specification.
- UA promoted mesodermal marker expression, SNAI pathway-mediated epithelial-mesenchymal transition (EMT), and lengthened G0/G1 phase in developing cells.
Conclusions:
- Uric acid (UA) plays a crucial role in promoting mesoderm differentiation during early embryonic development.
- UA enhances cardiac differentiation of human PSCs, offering a potential alternative to ascorbic acid (AA).
- UA levels may serve as a valuable indicator for congenital heart disease (CHD) detection in early fetal ultrasound screenings.
Abstract:
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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