DMD Pluripotent Stem Cell Derived Cardiac Cells Recapitulate in vitro Human Cardiac Pathophysiology.
Front. Bioeng. Biotechnol.. 2020-06-19; 8:
DOI: 10.3389/fbioe.2020.00535
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Jelinkova S(1)(2), Vilotic A(1), Pribyl J(3), Aimond F(4), Salykin A(1), Acimovic I(1), Pesl M(1)(2)(5), Caluori G(2)(5), Klimovic S(6), Urban T(1), Dobrovolna H(7), Soska V(7)(8), Skladal P(5)(6), Lacampagne A(4), Dvorak P(1)(2), Meli AC(1)(4), Rotrekl V(1)(2).
Author information:
(1)Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czechia.
(2)International Clinical Research Center ICRC, St. Anne’s University Hospital Brno, Brno, Czechia.
(3)CEITEC, Masaryk University, Brno, Czechia.
(4)PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France.
(5)First Department of Internal Medicine-Cardioangiology, Faculty of Medicine, Masaryk University, Brno, Czechia.
(6)Department of Biochemistry, Faculty of Science, Masaryk University, Brno, Czechia.
(7)Department of Clinical Biochemistry, St. Anne’s University Hospital of Brno, Brno, Czechia.
(8)Second Clinic of Internal Medicine, Masaryk University of Brno, Brno, Czechia.
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.
Copyright © 2020 Jelinkova, Vilotic, Pribyl, Aimond, Salykin, Acimovic, Pesl,
Caluori, Klimovic, Urban, Dobrovolna, Soska, Skladal, Lacampagne, Dvorak, Meli
and Rotrekl.