Diabetes in pregnancy affects fetus heart

Researchers have discovered how high glucose levels-whether caused by diabetes or other factors keep heart cells from maturing normally, this shows the reason why babies born to women with diabetes are more likely to develop congenital heart disease. When developing heart cells are exposed to high levels of glucose, the researchers found, the cells generate more building blocks of DNA than usual, which leads the cells to continue reproducing rather than mature.

High blood sugar levels are not only unhealthy for adults; they're unhealthy for developing fetuses.  the leading non-genetic risk factor for congenital heart disease is a mother having diabetes during 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. However, researchers have never been able to define the precise effect of glucose on the developing fetus.

Researchers used human embryonic stem cells to grow heart cardiomyocin 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. The researchers discovered that, when exposed to extra glucose, the cardiomyocytes over-activated the pentose phosphate pathway -a cellular process that, among other things, generates nucleotides, the building blocks of DNA.

In cells with high glucose levels, the pentose phosphate pathway made more nucleotides than usual. The scientists showed that the excess of building blocks kept the cells from maturing. By depleting glucose at the right point in development, we can limit the proliferation of the cells, which coaxes them to mature and makes the heart muscle stronger, The same thing occurred in pregnant mice with diabetes-the heart cells of fetuses divided quickly but matured slowly.
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How to turn scar tissue into healthy tissue

Limited therapeutic options and the heart's inability to regenerate healthy cells after heart attacks are parts of factors that cause sudden death in heart attack patients. Scientists are exploring ways to reprogram scar tissue cells into healthy heart muscle cells to reduce death.

Creation of cardiomyocytes with genetic signatures that closely mimic those found in healthy adult heart muscle cells can solve the problem. The other reprogramming approach leads to the creation of cardiomyocytes with more embryonic cell signatures.

The differences in the cardiomyocytes generated using these two methods are
Cardiomyocytes, the cells responsible for the beating of the heart, are essential to repairing the heart after injury. But after injury, such as a heart attack, many of these cells are irreversibly lost; they've been turned into scar tissue cells.

The replacement of these lost cells with patient-specific cardiomyocytes has gained attention as a potential therapy because existing healthy heart tissue better accepts these cells and because of increased recovery rates. Patient-specific cardiomyocytes also offer unique advantages for drug screens to help doctors identify each patient's drug type and dosage.

There are presently two widely practiced approaches to generate patient-specific cardiomyocytes.
In the first approach, an adult connective cell called a fibroblast is reprogrammed back into a naïve embryonic stem cell-like state. Once in this naïve state, the cell has the potential to develop into any cell type in the body, but scientists direct it to develop into a cardiomyocyte. These newly created cardiomyocytes are called induced pluripotent stem cell cardiomyocytes iPSC-CM.

In the second approach called direct cardiac reprogramming, a fibroblast is directly converted into a cardiomyocyte, without having to first be reprogrammed into a naïve embryonic stem cell. These new cardiomyocytes are called induced cardiomyocytes iCM. The researchers found that both methods resulted in cells with classic cardiomyocyte molecular features. However, by comparing the unique set of genes activated or not activated in each group of cells, the researchers found that iPSC-CMs more closely resembled embryonic cardiomyocytes, while iCMs more closely resembled adult cardiomyocytes.

Researchers also found that iPSC-CMs feature more active genes and a higher number of genes poised to be either activated or repressed a trait more commonly found in potent cells.
Metabolically, iPSC-CMs had a higher expression of glycolytic genes while iCMs had a higher expression of genes involved in fatty acid oxidation, the primary means of energy production in adult hearts.

In iPSC-CMs, heart muscle cells called sarcomeres, which give the heart a striated look, were less organized than in iCMs. The contractibility of cardiomyocytes as measured by the intake and removal of calcium was also greater in iCMs, suggesting that iCM cells are more mature than iPSC-CM cells.
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