J 2020

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

JELÍNKOVÁ, Šárka, Aleksandra VILOTIĆ, Jan PŘIBYL, Franck AIMOND, Anton SALYKIN et. al.

Basic information

Original name

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

Authors

JELÍNKOVÁ, Šárka (203 Czech Republic, belonging to the institution), Aleksandra VILOTIĆ (688 Serbia, belonging to the institution), Jan PŘIBYL (203 Czech Republic, belonging to the institution), Franck AIMOND (250 France), Anton SALYKIN (643 Russian Federation, belonging to the institution), Ivana AĆIMOVIĆ (688 Serbia, belonging to the institution), Martin PEŠL (203 Czech Republic), Guido CALUORI (380 Italy, belonging to the institution), Šimon KLIMOVIČ (203 Czech Republic, belonging to the institution), Tomáš URBAN (203 Czech Republic, belonging to the institution), Hana DOBROVOLNÁ (203 Czech Republic), Vladimír SOŠKA (203 Czech Republic), Petr SKLÁDAL (203 Czech Republic), Alain LACAMPAGNE (250 France), Petr DVOŘÁK (203 Czech Republic, belonging to the institution), Albano C. MELI (250 France) and Vladimír ROTREKL (203 Czech Republic, guarantor, belonging to the institution)

Edition

Frontiers in bioengineering and biotechnology, Laussane, Frontiers Media S.A. 2020, 2296-4185

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30401 Health-related biotechnology

Country of publisher

Switzerland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 5.890

RIV identification code

RIV/00216224:14110/20:00116091

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.3389/fbioe.2020.00535

UT WoS

000548398600001

Keywords in English

duchenne muscular dystrophy; DMD; human pluripotent stem cells; cardiomyocytes; intracellular calcium; excitation-contraction coupling; adrenergic response; cardiomyocyte death

Tags

14110115, 14110116, 14110513, CF NANO, podil, rivok

Tags

International impact, Reviewed
Změněno: 24/10/2024 14:10, Mgr. Adéla Pešková

Abstract

V originále

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.

Links

EF16_013/0001776, research and development project
Name: Česká infrastruktura pro integrativní strukturní biologii pro lidské zdraví
LM2018127, research and development project
Name: Česká infrastruktura pro integrativní strukturní biologii (Acronym: CIISB)
Investor: Ministry of Education, Youth and Sports of the CR
ROZV/28/LF12/2020, interní kód MU
Name: Analýza arytmogenicity a kardiotoxicity vybraných plicních léčiv na kardiomyocytech diferencovaných z kmenových buněk
Investor: Ministry of Education, Youth and Sports of the CR, Internal development projects
2SGA2744, interní kód MU
Name: CARDIOSTEM (Acronym: CARDIOSTEM)
Investor: South-Moravian Region, Incoming grants
7AMB13FR011, research and development project
Name: Přeprogramování somatických buněk darovaných pacienty s dědičnou Duchennovou svalovou dystrofií do kardiomyocytů - nahlédnutí do molekulární podstaty patologických dějů u dilatační kardiomyopatie nemocných DMD (Acronym: DUCHENSTEM)
Investor: Ministry of Education, Youth and Sports of the CR
Displayed: 23/12/2024 03:25