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How mom's diabetes affects the fetal heart
Congenital heart disease affects nearly 1 in 100 children born in the USA, making it our most common birth defect. The severity of its symptoms and causes varies, ranging from a slightly weakened heart muscle with no symptoms to severe heart deformations that require surgery.
Researchers at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at the University of California at Los Angeles (UCLA) have discovered how high glucose levels — whether caused by diabetes or other factors — keep heart cells from maturing normally.
Atsushi "Austin" Nakano, UCLA associate professor of molecular, cell, and developmental biology and member of the Broad Stem Cell Research Center, led a study published in the journal eLife explaining a root cause of damage. When developing heart cells are exposed to high levels of glucose, they generate more building blocks of DNA than usual. This leads them to continue reproducing rather than to mature.
"High blood sugar levels are not only unhealthy for adults, they are unhealthy for developing fetuses," explains Nakano. "Understanding the mechanism by which high blood sugar levels cause disease in the fetus may eventually lead to new therapies."
These findings help explain why babies born to women with diabetes are more likely to develop congenital heart disease.
Although genetics plays a large role in the development of congenital heart disease, the leading non-genetic risk factor for the disease is a mother with diabetes in pregnancy. Babies born to women with high levels of glucose in their blood during pregnancy are two to five times more likely to develop the disorder than other babies. Researchers had never been able to define the precise effect of glucose on a developing fetus before now.
Nakano and his colleagues used human embryonic stem cells to grow heart muscle cells, or cardiomyocytes, in the lab and then exposed them to varying levels of glucose. Cells that were exposed to small amounts of glucose matured normally. But cardiomyocytes that had been mixed with high levels of glucose matured late or failed to mature altogether, and instead generated more immature cells.
Researchers discovered that, when exposed to extra glucose, cardiomyocytes over-activated the pentose phosphate pathway — a cellular process that generates nucleotides, the building blocks of DNA. In cells with high glucose levels, the pentose phosphate pathway made more nucleotides than usual. This excess of building blocks keeps cardiomyocytes from maturing.
"More nutrition is generally thought to be better for cells, but here we see the exact opposite," says Nakano. "By depleting glucose at the right point in development, we can limit the proliferation of cardiomyocyte cells, which coaxes them to mature and make the heart muscle stronger."
Additonal research by the group observed the same process at work in pregnant mice with diabetes, in that heart cells of mouse fetuses divided quickly but matured slowly. Nakano believes his finding could lead to better methods of making cardiomyocytes from stem cells. Today most protocols for lab generated cardiomyocytes lead to immature cells. However, targeting the pentose phosphate pathway could help generate more mature cells for the regeneration of heart cells, as well as for other research purposes.
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.
Authors: Haruko Nakano Itsunari Minami Daniel Braas Herman Pappoe Xiuju Wu Addelynn Sagadevan Laurent Vergnes Kai Fu Marco Morselli Christopher Dunham Xueqin Ding Adam Z Stieg James K Gimzewski Matteo Pellegrini Peter M Clark Karen Reue Aldons J Lusis Bernard Ribalet Siavash K Kurdistani Heather Christofk Norio Nakatsuji Atsushi Nakano
The pentose phosphate pathway as a target for cardiac maturation is covered by a provisional patent application filed by the UCLA Technology Development Group on behalf of the University of California Regents, with Austin Nakano and Haruko Nakano, a UCLA assistant researcher, as inventors.
The research was supported by grants from the Oppenheimer Foundation, the National Institutes of Health, the National Center for Research Resources and the Chinese Scholarship Council of Chemistry and Chemical Engineering, as well as funding from the Center for Duchenne Muscular Dystrophy at UCLA and the Broad Stem Cell Research Center.
The research was supported by funding from MINECO, through ERDF, and from the Catalan Government.
The Jackson Laboratory is an independent, nonprofit biomedical research institution based in Bar Harbor, Maine, with a National Cancer Institute-designated Cancer Center, a facility in Sacramento, Calif., and a genomic medicine institute in Farmington, Conn. It employs more than 2,000 staff, and its mission is to discover precise genomic solutions for disease and empower the global biomedical community in the shared quest to improve human health.
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Human heart cells grown from stem cells show less robust muscle fibers (green)
n high glucose conditions (left) compared to reduced glucose conditions (right).
Image credit: UCLA Broad Stem Cell Research Center/eLife.