DMD Pluripotent Stem Cell Derived Cardiac Cells Recapitulate in vitro Human Cardiac Pathophysiology
Duchenne muscular dystrophy (DMD) is a severe genetic disorder characterized by the lack of functional dystrophin. DMD is associated with progressive dilated cardiomyopathy, eventually leading to heart failure as the main cause of death in DMD patients. Although several molecular mechanisms leading to the DMD cardiomyocyte (DMD-CM) death were described, mostly in mouse model, no suitable human CM model was until recently available together with proper clarification of the DMD-CM phenotype and delay in cardiac symptoms manifestation. We obtained several independent dystrophin-deficient human pluripotent stem cell (hPSC) lines from DMD patients and CRISPR/Cas9-generated DMD gene mutation. We differentiated DMD-hPSC into cardiac cells (CC) creating a human DMD-CC disease model. We observed that mutation-carrying cells were less prone to differentiate into CCs. DMD-CCs demonstrated an enhanced cell death rate in time. Furthermore, ion channel expression was altered in terms of potassium (Kir2.1 overexpression) and calcium handling (dihydropyridine receptor overexpression). DMD-CCs exhibited increased time of calcium transient rising compared to aged-matched control, suggesting mishandling of calcium release. We observed mechanical impairment (hypocontractility), bradycardia, increased heart rate variability, and blunted β-adrenergic response connected with remodeling of β-adrenergic receptors expression in DMD-CCs. Overall, these results indicated that our DMD-CC models are functionally affected by dystrophin-deficiency associated and recapitulate functional defects and cardiac wasting observed in the disease. It offers an accurate tool to study human cardiomyopathy progression and test therapies in vitro.
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AUTHORS (17)
CATEGORIES
- Bioprocessing, Bioproduction and Bioproducts
- Industrial Biotechnology Diagnostics (incl. Biosensors)
- Industrial Microbiology (incl. Biofeedstocks)
- Industrial Molecular Engineering of Nucleic Acids and Proteins
- Industrial Biotechnology not elsewhere classified
- Medical Biotechnology Diagnostics (incl. Biosensors)
- Biological Engineering
- Regenerative Medicine (incl. Stem Cells and Tissue Engineering)
- Medical Biotechnology not elsewhere classified
- Agricultural Marine Biotechnology
- Biomaterials
- Biomechanical Engineering
- Biotechnology
- Biomarkers
- Biomedical Engineering not elsewhere classified
- Genetic Engineering
- Synthetic Biology
- Bioremediation
- Medical Molecular Engineering of Nucleic Acids and Proteins