Small molecule activators and inhibitors of retinoic acid (RA) to create chamber-specific myocytes from pluripotent stem cells without cell sorting.
- Produces highly-enriched, subtype-specific populations of cardiac myocytes.
- Eliminates need for cell-sorting.
- Does not require transgenic changes to the human stem cells.
Cardiovascular disease (CVD) is the #1 cause of death worldwide in men, women and children, claiming more than 17 million lives each year. Congestive heart failure and acute myocardial infarction (heart attack) present great challenges for therapy development because human heart, once damaged, cannot regenerate itself. CVD irreversibly damages the muscle cells of the heart, cardiomyocytes, which triggers a cascade of detrimental events and leads to heart failure. Pluripotent human stem cells can give rise to unlimited quantities of new cardiomyocytes in a dish, and thus represent excellent therapeutic modality. However, the cardiac differentiation protocol leads to an indiscriminate blend of all types of cardiac myocytes, including atrial and pacemaker cells as well as ventricular myocytes. For therapeutic applications, this heightens arrhythmogenic risks and lowers functional benefit. For drug discover, heterogeneous cardiomyocyte subtypes leads to high attrition rates due to false positives or negatives.
Emory University researchers exploited the wealth of knowledge in embryology as it relates to signaling pathways crucial for human heart development. They found that time and dose-dependent control of retinoic acid pathway can specify the types of cardiomyocytes differentiated from human pluripotent stem cells. With this method, the team succeeded in guiding the differentiation of human pluripotent stem cells to left ventricular myocytes, the major cell type depleted in heart failure, or atrial myocytes. The new method utilizes small molecules without the need for manipulation of the genome. This signifies the generalizability and safety of this technology across all patient-derived stem cell lines for both therapeutic and drug discovery applications. The technology has the capability to improve the specificity and effectiveness of drugs by more accurately evaluating how they will react to either left ventricular or atrial chambers of the heart in a patient-tailored manner.
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Generated de novo atrial and ventricular cardiomyocytes accurately resemble the native human atrial and ventricular cardiomyocytes, respectively.