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Mechanistic new insight and new drugs to treat Hypertrophic Cardiomyopathy

By using the power of stem cell technology and recent development in regenerative biology, we are able to reprogram a normal somatic cell into cardiac stem cells, which are beating like normal heart cells. We can gain a better mechanistic understanding of heart failure disease by using stem cell derived patient heart cells, which will further help to develop drugs to prevent this disease. Because animal models do not recapitulate all the features of human heart disease, which makes difficult to understand the pathobiology and limits the development of new therapy.
Hypertrophic cardiomyopathy is a most common genetic heart muscle disease affecting 1 in 500 people around the world. This disease is popularly called familial hypertrophic cardiomyopathy because it is commonly observed in family members of the affected individual. In this disease, the gene encoding the heart muscles get mutated and produce abnormal heart muscle protein. Abnormal heart muscle proteins, altered contraction and relaxation resulting into thicker heart muscles and that leads to hypertrophy. Excess cardiac muscle thickness leads stiffer heart and reduced function with high morbidity and mortality. Because there are lots of genetic variations in the heart muscle protein profile and their relative abundance in rodent animal models to human beings. To understand the fundamental mechanism behind the genetic mutations rodent models are not ideal, besides it’s very difficult to get human heart tissues from the patients. To circumvent these hurdles, we can generate heart cells from patient skin or blood cells. By these stem cell derived cardiomyocytes it is very convenient for disease modeling and drug screening, I have been studying the new insights of disease mechanism with suitable therapy. Little is known about the molecular genetics of hypertrophic cardiomyopathy. From heart failure clinic, we found a family with genetic hypertrophic cardiomyopathy. Blood samples are collected from all family members and these blood cells are subjected to reprogramming to get stem cells. This patient derived stem cells are further cultured to get beating heart cells. We characterized these heart cells from all family members and found that those family members with hypertrophic cardiomyopathy have bigger heart cells compared to healthy ones. This study demonstrates new insights of the disease pathogenesis and the drug screening to discover new drugs to treat the hypertrophic cardiomyopathy.


Modeling and study of the mechanism of dilated cardiomyopathy using induced pluripotent stem cells derived from individuals with Duchenne muscular dystrophy.

Abstract: Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene (DMD), and is characterized by progressive weakness in skeletal and cardiac muscles. Currently, dilated cardiomyopathy due to cardiac muscle loss is one of the major causes of lethality in late-stage DMD patients. To study the molecular mechanisms underlying dilated cardiomyopathy in DMD heart, we generated cardiomyocytes (CMs) from DMD and healthy control induced pluripotent stem cells (iPSCs). DMD iPSC-derived CMs (iPSC-CMs) displayed dystrophin deficiency, as well as the elevated levels of resting Ca(2+), mitochondrial damage and cell apoptosis. Additionally, we found an activated mitochondria-mediated signaling network underlying the enhanced apoptosis in DMD iPSC-CMs. Furthermore, when we treated DMD iPSC-CMs with the membrane sealant Poloxamer 188, it significantly decreased the resting cytosolic Ca(2+) level, repressed caspase-3 (CASP3) activation and consequently suppressed apoptosis in DMD iPSC-CMs. Taken together, using DMD patient-derived iPSC-CMs, we established an in vitro model that manifests the major phenotypes of dilated cardiomyopathy in DMD patients, and uncovered a potential new disease mechanism. Our model could be used for the mechanistic study of human muscular dystrophy, as well as future preclinical testing of novel therapeutic compounds for dilated cardiomyopathy in DMD patients.

Pub.: 21 Mar '15, Pinned: 02 Aug '17