Informace o publikaci

DMD Pluripotent Stem Cell Derived Cardiac Cells Recapitulate in vitro Human Cardiac Pathophysiology

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JELÍNKOVÁ Šárka VILOTIĆ Aleksandra PŘIBYL Jan AIMOND Franck SALYKIN Anton AĆIMOVIĆ Ivana PEŠL Martin CALUORI Guido KLIMOVIČ Šimon URBAN Tomáš DOBROVOLNÁ Hana SOŠKA Vladimír SKLÁDAL Petr LACAMPAGNE Alain DVOŘÁK Petr MELI Albano C. ROTREKL Vladimír

Rok publikování 2020
Druh Článek v odborném periodiku
Časopis / Zdroj Frontiers in bioengineering and biotechnology
Fakulta / Pracoviště MU

Lékařská fakulta

Citace
www https://www.frontiersin.org/articles/10.3389/fbioe.2020.00535/full
Doi http://dx.doi.org/10.3389/fbioe.2020.00535
Klíčová slova duchenne muscular dystrophy; DMD; human pluripotent stem cells; cardiomyocytes; intracellular calcium; excitation-contraction coupling; adrenergic response; cardiomyocyte death
Popis 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 beta-adrenergic response connected with remodeling of beta-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 therapiesin vitro.
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