Roles of Mesp1 gene

Researchers at the Université libre de Bruxelles and University of Cambridge identified the role of key gene Mesp1 in the earliest step of cardiovascular lineage segregation. This discovery may help to better understand congenital heart defects. The heart is the first organ that forms during development and contains four regions (ventricles and atria), which contain cells that perform specialized functions: the beating cardiomyocytes ensure the pumping activity, vascular cells represent the inner lining and blood vessels, and the pacemaker cells regulate the heartbeat.

Unless the progenitor cells are specified at the correct time, migrate to the correct location, and differentiate into the correct cell types, severe malformations of the heart occur. In human patients, these are recognized as congenital heart diseases, which represent the most common cause of severe birth defects in newborn babies. Previous studies had shown that a diverse range of heart progenitor cells arises from different pools of cells expressing the Mesp1 gene. However, it remained unclear how the various progenitors can be distinguished at the molecular level, and what molecular mechanisms promote specification into a particular heart region or cardiac lineage.

Researchers led by Pr. Cédric Blanpain, Laboratory of Stem Cells and Cancer, Université libre de Bruxelles, Belgium, and Pr. Berthold Göttgens, the University of Cambridge, identified the role of Mesp1 in the earliest step of cardiovascular lineage segregation by single cell molecular profiling and lineage tracking. Fabienne Lescroart and colleagues isolated Mesp1 expressing cells at different stages of embryonic development and performed single cell transcriptomic analysis of these early cardiac progenitors to identify the molecular features associated with regional and cell type identity of cardiac progenitors.

They demonstrated that the different populations of cardiac progenitors are molecularly distinct. To determine the role of the transcription factor Mesp1 in regulating the cardiovascular differentiation program and the heterogeneity of early cardiovascular progenitors, they also performed single cell molecular profiling of these early progenitors in a Mesp1 deficient context. These experiments showed that Mesp1 is required for the exit from the pluripotent state and the induction of the cardiovascular gene expression program.

Bioinformatic analysis identified, among these early Mesp1 progenitors, distinct populations of cells corresponding to progenitors committed to different cell lineages and regions of the heart, identifying the molecular features associated with early lineage restriction and regional segregation of the heart. While progenitor cells are not yet differentiated, this new analysis shows that cardiovascular progenitors are already "primed" or pre-specified to give rise to cardiac muscle cells or vascular cells. The researchers found that these different populations are also born at different time points and are located at specific locations at this early stage of development.

The researchers have identified the earliest branching point between the cardiac and vascular lineages, and shown that Notch1 marks the early progenitor committed to the vascular lineage during early embryonic development. Understanding the molecular features associated with early cardiovascular lineage commitment and heart regions will be important to design new strategies to instruct cardiovascular progenitors to adopt cardiac or vascular identity from different heart regions that can be used for cellular therapy of cardiac diseases.
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Vaping can cause birth defects

Vaping while pregnant could cause babies to be born with disfiguring birth defects to their faces and heads. Exposure to e-cigarette vapor damaged cells that would eventually become facial features in ways that could cause facial clefts and uneven growth of facial structures. The Centers for Disease  Control and Prevention CDC and doctors already recommend that no form of smoking – including vaping – is safe for pregnant women.

As many as 19.4 percent of young adults thought that e-cigarettes caused ‘no harm,’ according to CDC data collected between 2013 and 2014. More than half of the same age group believed that they were only ‘moderately harmful.’ Studies have shown that e-cigarette vapor does have fewer toxins, but the products are so new that their effects aren’t fully understood.

They discovered that the mixture of liquids to create the novel flavors of e-cigarette vapor were responsible for the worst damage to the developing fetus. Most flavors led to only minor effects, like slightly smaller than normal faces. But one unnamed flavor in particular consistently caused the most damage. All of the frogs exposed to that flavor had significant facial clefts.

E-cigarettes use a heating mechanism to heat e-liquids and convert them into flavored vapor. The liquids contain nicotine, as well as propylene, glycol, vegetable glycerine and flavoring compounds. The ingredients used to make the various flavors are a bit of a mystery. Researchers  analyzed 159 varieties of flavored vape liquids, and found that more than two thirds used a compound called diacetyl, which is linked to a popcorn lung.

Previous research linked flavoring in e-liquids to heart defects in developing zebrafish, brain development delays in mice, and the release of at least two carcinogens. The researchers tested six different e-liquids, with nicotine strengths varying from six mg/ml to 24 and one or more flavoring additives. Two varieties had only one flavor each: red tobacco and menthol. They also tested a liquid flavored with both milk and dark chocolate, and one with melon and candy.

The most dramatic defects were tied to the two liquids with the greatest number of different flavors. One used strawberry, almond, caramel, vanilla, biscuit and Vienna cream flavorings, and the other had cereal, berries, cream and citrus. Both of the many-flavored varieties led to dramatically cleft faces or other facial birth defects in the frogs they were tested on.

Facial and mouth clefts are gaps in the middle of the face that can affect both soft muscle and skin tissue and bones. They are rare in humans, effecting only about 1 in every 150,000 babies born worldwide. Depending on how severe the cleft is, they may be reparable with surgery, but if left untreated can also make it difficult for people with cleft faces and palates to eat, make them prone to ear infections and hearing loss, speech and language impairments and dental problems.
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Genes and environment can increase the risk of congenital heart defects

Infants of mothers with diabetes have increased risk of congenital heart defects. Such developmental defects are likely caused by a combination of genetic and environmental factors. The molecular mechanisms by which maternal diabetes disrupts normal heart development in genetically susceptible individuals remain unclear.

The Cardiovascular Research describe a gene-environment interaction resulting in congenital heart defects in both mouse and fly model systems. Interaction between two genes, Endothelial Nitric Oxide Synthase and Notch1, would result in more severe types of congenital heart defects in animal models. Diabetes is known to be associated with decreased nitric oxide levels in blood vessels.

Maternal diabetes, in combination with a mutation in Notch1, would result in a higher risk of congenital heart disease.
Researchers showed that maternal hyperglycemia reduces the chromatin accessibility of the Endothelial Nitric Oxide Synthase gene, resulting in decreased nitric oxide production.

This loss of nitric oxide is associated with an increase in expression of Jarid2, a known repressor of the Notch1 gene. This directly inhibited Notch1 expression to levels below a critical threshold necessary for normal heart development. This study lends support to a gene-environment interaction model where maternal hyperglycemia raises the risk of congenital heart defects by reducing Notch1 expression.

The results reveal the epigenetic machinery by which maternal hyperglycemia disrupts the Nitric Oxide and Notch1 signaling pathways, leading to congenital heart defects. Infants that are exposed to hyperglycemia develop a congenital heart defect, which supports the idea that there are genetically susceptible individuals.
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Fever in early pregnancy causes facial birth defects

Researchers have known for decades that fevers in the first trimester of pregnancy increase the risk for some heart defects and facial deformities such as cleft lip or palate in developing fetus. Researchers now have evidence indicating that fever is responsible for interferes with the development of the heart and jaw during the first three to eight weeks of pregnancy.

The results suggest a portion of congenital birth defects could be prevented by lowering the mother's fever with the use of acetaminophen during the first trimester. Women who are planning to become pregnant are advise to start taking prenatal vitamins and folic acid, they should take drug that can reduce the effects of fever if they have fever during the first trimester

Acetaminophen (Tylenol), which has been studied extensively and determined to be safe during the first trimester is recommended. The use of nonsteroidal anti-inflammatory drugs NSAIDs such as ibuprofen and aspirin also reduce fevers, but some NSAIDs are not safe to use during the later stages of pregnancy.

To observe how fever impacts a developing fetus, the researchers studied zebra embryo. Among their discoveries, they found that neural crest cells, the cells that are critical building blocks for the heart, face and jaw - contain temperature-sensitive properties. These neural crest cells contain temperature-sensitive ion channels that typically are found in the sensory neurons. They're the channels that, when you stick your hand in a hot cup of water, tell your body the temperature has changed.

The researchers engineered a noninvasive magnet-based technology to create fever-like conditions in two specific temperature-sensitive ion channels called TRPV1 and TRPV4 in the neural crest cells involved in developing the heart and face. When those neural crest cells were subjected to conditions mimicking a transient fever, the embryos developed craniofacial irregularities and heart defects, including double outlet right ventricle, Tetralogy of Fallot and other outflow obstructions. The type of defect depends on whether the fever occurs during heart development or head and face development.
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