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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Anti-malarial drug for Zika virus treatment

Medication used to prevent and treat malaria may also be effective for Zika virus. The drug, called chloroquine, has a long history of safe use during pregnancy. Zika causes mild flu-like symptoms. But in pregnant women, the virus can cause serious birth defects in babies-including microcephaly-a neurological condition in which newborns have unusually small heads and fail to develop properly.

Presently, there is no treatment or way to reverse the condition. The latest research suggests the anti-malaria drug chloroquine may be an effective drug to treat and prevent Zika infections. Reseachers examined the effect of chloroquine in human brain organoids and pregnant mice infected with the virus, and found the drug markedly reduced the amount of Zika virus in maternal blood and neural progenitor cells in the fetal brain.

Pregnant mice received chloroquine through drinking water in dosages equivalent to acceptable levels used in humans. Although chloroquine did not completely clear Zika from infected mice it did reduce the viral load, suggesting it could limit the neurological damage found in newborns infected by the virus.
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Transplanted hematopoietic stem cells reverse damage caused by neuro-muscular disorder

Single infusion of wildtype hematopoietic stem and progenitor cells (HSPCs) into a mouse model of Friedreich's ataxia (FA) measurably halted cellular damage caused by the degenerative disease. Friedreich's ataxia is an inherited, degenerative neuromuscular disorder that initially impairs motor function, such as gait and coordination, but can lead to scoliosis, heart disease, vision loss and diabetes. Cognitive function is not affected.

The disease is progressively debilitating, and ultimately requires full-time use of a wheelchair. FA is caused by reduced expression of a mitochondrial protein called frataxin (FXN) due to a two mutated or abnormal copies of the FXN gene. Researchers used a transgenic mouse model that expresses two mutant human FXN transgenes, and exhibits the resulting progressive neurological degeneration and muscle weakness.

Human hematopoietic stem and progenitor cells (HSPCs), derived from bone marrow, have become a primary vehicle for efforts to replace or regenerate cells destroyed by a variety of diseases. Transplanting wildtype or normal mouse HSPCs resulted in long-term kidney, eye and thyroid preservation in a mouse model of cystinosis, another genetic disorder.

Researchers transplanted wildtype HSPCs into an FA mouse model, reporting that the HSPCs engrafted and soon differentiated into macrophages in key regions of the mice's brain and spinal cord where they appeared to transfer wildtype FXN into deficient neurons and muscle cells. Transplantation of wildtype mouse HSPCs essentially rescued FA-impacted cells expression was restored. Mitochondrial function in the brains of the transgenic mice normalized, as did in the heart. There was also decreased skeletal muscle atrophy.
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