Cardiomyocytes derived from pluripotent stem cells recapitulate electrophysiological characteristics of an overlap syndrome of cardiac sodium channel disease.
BACKGROUND
Pluripotent stem cells (PSCs) offer a new paradigm for modeling genetic cardiac diseases, but it is unclear whether mouse and human PSCs can truly model both gain- and loss-of-function genetic disorders affecting the Na(+) current (I(Na)) because of the immaturity of the PSC-derived cardiomyocytes. To address this issue, we generated multiple PSC lines containing a Na(+) channel mutation causing a cardiac Na(+) channel overlap syndrome.


RESULTS
Induced PSC (iPSC) lines were generated from mice carrying the Scn5a(1798insD/+) (Scn5a-het) mutation. These mouse iPSCs, along with wild-type mouse iPSCs, were compared with the targeted mouse embryonic stem cell line used to generate the mutant mice and with the wild-type mouse embryonic stem cell line. Patch-clamp experiments showed that the Scn5a-het cardiomyocytes had a significant decrease in I(Na) density and a larger persistent I(Na) compared with Scn5a-wt cardiomyocytes. Action potential measurements showed a reduced upstroke velocity and longer action potential duration in Scn5a-het myocytes. These characteristics recapitulated findings from primary cardiomyocytes isolated directly from adult Scn5a-het mice. Finally, iPSCs were generated from a patient with the equivalent SCN5A(1795insD/+) mutation. Patch-clamp measurements on the derivative cardiomyocytes revealed changes similar to those in the mouse PSC-derived cardiomyocytes.


CONCLUSIONS
Here, we demonstrate that both embryonic stem cell- and iPSC-derived cardiomyocytes can recapitulate the characteristics of a combined gain- and loss-of-function Na(+) channel mutation and that the electrophysiological immaturity of PSC-derived cardiomyocytes does not preclude their use as an accurate model for cardiac Na(+) channel disease.
Department of Anatomy and Embryology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The Netherlands. r.p.davis@lumc.nl
Richard P
RP
Davis
Simona
S
Casini
Cathelijne W
CW
van den Berg
Maaike
M
Hoekstra
Carol Ann
CA
Remme
Cheryl
C
Dambrot
Daniela
D
Salvatori
Dorien Ward-van
DW
Oostwaard
Arthur A M
AA
Wilde
Connie R
CR
Bezzina
Arie O
AO
Verkerk
Christian
C
Freund
Christine L
CL
Mummery
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D018920:Coculture Techniques; D055724:Electrophysiological Phenomena / Q000235:genetics; D006331:Heart Diseases / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000473:pathology* / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation / Q000235:genetics; D032383:Myocytes, Cardiac / Q000473:pathology* / Q000502:physiology*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology; D013577:Syndrome
D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; C568321:Scn5a protein, mouse; D015222:Sodium Channels