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

S. Jelinkova, A. Vilotic, J. Pribyl, F. Aimond, A. Salykin, I. Acimovic, M. Pesl, G. Caluori, S. Klimovic, T. Urban, H. Dobrovolna, V. Soska, P. Skladal, A. Lacampagne, P. Dvorak, AC. Meli, V. Rotrekl,

. 2020 ; 8 (-) : 535. [pub] 20200619

Jazyk angličtina Země Švýcarsko

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc20022086

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.

Citace poskytuje Crossref.org

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$a Jelinkova, Sarka $u Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czechia. International Clinical Research Center ICRC, St. Anne's University Hospital Brno, Brno, Czechia.
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$a 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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$a Vilotic, Aleksandra $u Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czechia.
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$a Pribyl, Jan $u CEITEC, Masaryk University, Brno, Czechia.
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$a Aimond, Franck $u PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France.
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$a Salykin, Anton $u Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czechia.
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$a Aćimović, Ivana $u Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czechia. $7 xx0314769
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$a Pesl, Martin $u Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czechia. International Clinical Research Center ICRC, St. Anne's University Hospital Brno, Brno, Czechia. First Department of Internal Medicine-Cardioangiology, Faculty of Medicine, Masaryk University, Brno, Czechia.
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$a Caluori, Guido $u International Clinical Research Center ICRC, St. Anne's University Hospital Brno, Brno, Czechia. First Department of Internal Medicine-Cardioangiology, Faculty of Medicine, Masaryk University, Brno, Czechia.
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$a Klimovic, Simon $u Department of Biochemistry, Faculty of Science, Masaryk University, Brno, Czechia.
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$a Urban, Tomas $u Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czechia.
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$a Dobrovolna, Hana $u Department of Clinical Biochemistry, St. Anne's University Hospital of Brno, Brno, Czechia.
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$a Soska, Vladimir $u Department of Clinical Biochemistry, St. Anne's University Hospital of Brno, Brno, Czechia. Second Clinic of Internal Medicine, Masaryk University of Brno, Brno, Czechia.
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$a Skladal, Petr $u First Department of Internal Medicine-Cardioangiology, Faculty of Medicine, Masaryk University, Brno, Czechia. Department of Biochemistry, Faculty of Science, Masaryk University, Brno, Czechia.
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$a Lacampagne, Alain $u PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France.
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$a Dvorak, Petr $u Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czechia. International Clinical Research Center ICRC, St. Anne's University Hospital Brno, Brno, Czechia.
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$a Meli, Albano C $u Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czechia. PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France.
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$a Rotrekl, Vladimir $u Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czechia. International Clinical Research Center ICRC, St. Anne's University Hospital Brno, Brno, Czechia.
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