Abstract
The heart switches its energy substrate from glucose to fatty acids at birth, and maternal hyperglycemia is associated with congenital heart disease. However, little is known about how blood glucose impacts heart formation. Using a chemically defined human pluripotent stem-cell-derived cardiomyocyte differentiation system, we found that high glucose inhibits the maturation of cardiomyocytes at genetic, structural, metabolic, electrophysiological, and biomechanical levels by promoting nucleotide biosynthesis through the pentose phosphate pathway. Blood glucose level in embryos is stable in utero during normal pregnancy, but glucose uptake by fetal cardiac tissue is drastically reduced in late gestational stages. In a murine model of diabetic pregnancy, fetal hearts showed cardiomyopathy with increased mitotic activity and decreased maturity. These data suggest that high glucose suppresses cardiac maturation, providing a possible mechanistic basis for congenital heart disease in diabetic pregnancy.
Highlights
Congenital heart disease (CHD) is the most common type of birth defect affecting 0.8% of human live births (Fahed et al, 2013)
Glucose reduction promotes hESC-CM differentiation hESC-CMs were differentiated in monolayer in a chemically defined condition, reproducibly yielding 90% of MF20+ cardiomyocytes at day 14 with multiple cell lines including WA09 (H9) and
We investigated the role of glucose in cardiac formation, and discovered (1) that glucose dose-dependently inhibits cardiac maturation in hESC-CMs, (2) that the maturationinhibitory effect is dependent on nucleotide biosynthesis via the phosphate pathway (PPP), (3) that the developing heart accomplishes intracellular glucose starvation by limiting glucose uptake in late gestational stages during normal embryogenesis, and (4) that perturbation of the environmental glucose level in diabetic pregnancy affects natural cardiomyocyte maturation in vivo
Summary
Congenital heart disease (CHD) is the most common type of birth defect affecting 0.8% of human live births (Fahed et al, 2013). Among the non-genetic factors that influence the fetal heart, maternal hyperglycemia is the most common medical condition, associated with a 2–5-fold increase in CHD independent of genetic contributors (Centers for Disease Control, 1990; Simeone et al, 2015; Yogev and Visser, 2009). Diabetic pregnancy is often accompanied by maternal complications including vasculopathy, neuropathy, and insulin resistance, which potentially affect fetal cardiac formation indirectly. These systemic complications are often subclinical, hindering the dissection of the pathomechanism of CHD in diabetic pregnancy. Despite the established association between maternal hyperglycemia and malformation of the fetal heart, little is known about how glucose levels impact cardiomyocyte development and how hyperglycemia affects heart formation in diabetic pregnancy (Gaspar et al, 2014)
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call