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

@article{1672178,
   author = {Jelínková, Šárka and Vilotić, Aleksandra and Přibyl, Jan and Aimond, Franck and Salykin, Anton and Aćimović, Ivana and Pešl, Martin and Caluori, Guido and Klimovič, Šimon and Urban, Tomáš and Dobrovolná, Hana and Soška, Vladimír and Skládal, Petr and Lacampagne, Alain and Dvořák, Petr and Meli, Albano C. and Rotrekl, Vladimír},
   article_location = {Laussane},
   article_number = {June 2019},
   doi = {http://dx.doi.org/10.3389/fbioe.2020.00535},
   keywords = {duchenne muscular dystrophy; DMD; human pluripotent stem cells; cardiomyocytes; intracellular calcium; excitation-contraction coupling; adrenergic response; cardiomyocyte death},
   language = {eng},
   issn = {2296-4185},
   journal = {Frontiers in bioengineering and biotechnology},
   title = {DMD Pluripotent Stem Cell Derived Cardiac Cells Recapitulate in vitro Human Cardiac Pathophysiology},
   url = {https://www.frontiersin.org/articles/10.3389/fbioe.2020.00535/full},
   volume = {8},
   year = {2020}
}

TY  - JOUR
ID  - 1672178
AU  - 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
PY  - 2020
TI  - DMD Pluripotent Stem Cell Derived Cardiac Cells Recapitulate in vitro Human Cardiac Pathophysiology
JF  - Frontiers in bioengineering and biotechnology
VL  - 8
IS  - June 2019
SP  - 1-19
EP  - 1-19
PB  - Frontiers Media S.A.
SN  - 22964185
KW  - duchenne muscular dystrophy
KW  - DMD
KW  - human pluripotent stem cells
KW  - cardiomyocytes
KW  - intracellular calcium
KW  - excitation-contraction coupling
KW  - adrenergic response
KW  - cardiomyocyte death
UR  - https://www.frontiersin.org/articles/10.3389/fbioe.2020.00535/full
L2  - https://www.frontiersin.org/articles/10.3389/fbioe.2020.00535/full
N2  - 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.
ER  - 

JELÍNKOVÁ, Šárka, Aleksandra VILOTI$\backslash$'C, Jan PŘIBYL, Franck AIMOND, Anton SALYKIN, Ivana A$\backslash$'CIMOVI$\backslash$'C, Martin PEŠL, Guido CALUORI, Šimon KLIMOVIČ, Tomáš URBAN, Hana DOBROVOLNÁ, Vladimír SOŠKA, Petr SKLÁDAL, Alain LACAMPAGNE, Petr DVOŘÁK, Albano C. MELI and Vladimír ROTREKL. DMD Pluripotent Stem Cell Derived Cardiac Cells Recapitulate in vitro Human Cardiac Pathophysiology. \textit{Frontiers in bioengineering and biotechnology}. Laussane: Frontiers Media S.A., 2020, vol.~8, June 2019, p.~1-19. ISSN~2296-4185. Available from: https://dx.doi.org/10.3389/fbioe.2020.00535.