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Functional hyperactivity in long OT syndrome type 1 pluripotent stem cell-derived sympathetic neurons
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics. Department of Physiology, University of Auckland, Auckland, New Zealand; Manaaki Manawa Centre for Heart Research, University of Auckland, Auckland, New Zealand; Department of Paediatric and Congenital Cardiac Services, Starship Children's Hospital, Auckland, New Zealand; Cardiac Inherited Disease Group (CIDG), Auckland, New Zealand.ORCID iD: 0000-0002-9323-3166
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.ORCID iD: 0000-0001-9655-7783
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2021 (English)In: American Journal of Physiology. Heart and Circulatory Physiology, ISSN 0363-6135, E-ISSN 1522-1539, Vol. 321, no 1, p. H217-H227Article in journal (Refereed) Published
Abstract [en]

Sympathetic activation is an established trigger of life-threatening cardiac events in long QT syndrome type 1 (LQT1). KCNQ1 loss-of-function variants, which underlie LQT1, have been associated with both cardiac arrhythmia and neuronal hyperactivity pathologies. However, the LQT1 sympathetic neuronal phenotype is unknown. Here, we aimed to study human induced pluripotent stem cell (hiPSC)-derived sympathetic neurons (SNs) to evaluate neuronal functional phenotype in LQT1. We generated hiPSC-SNs from two patients with LQT1 with a history of sympathetically triggered arrhythmia and KCNQ1 loss-of-function genotypes (c.781_782delinsTC and p.S349W/p.R518X). Characterization of hiPSC-SNs was performed using immunohistochemistry, enzyme-linked immunosorbent assay, and whole cell patch clamp electrophysiology, and functional LQT1 hiPSC-SN phenotypes compared with healthy control (WT) hiPSC-SNs. hiPSC-SNs stained positive for tyrosine hydroxylase, peripherin, KCNQ1, and secreted norepinephrine. hiPSC-SNs at 60 +/- 2.2 days in vitro had healthy resting membrane potentials (-60 +/- 1.3 mV), and fired rapid action potentials with mature kinetics in response to stimulation. Significant hyperactivity in LQT1 hiPSC-SNs was evident via increased norepinephrine release, increased spontaneous action potential frequency, increased total inward current density, and reduced afterhyperpolarization, compared with age-matched WT hiPSC-SNs. A significantly higher action potential frequency upon current injection and larger synaptic current amplitudes in compound heterozygous p.S349W/p.R518X hiPSC-SNs compared with heterozygous c.781_782delinsTC hiPSC-SNs was also observed, suggesting a potential genotype-phenotype correlation. Together, our data reveal increased neurotransmission and excitability in heterozygous and compound heterozygous patient-derived LQT1 sympathetic neurons, suggesting that the cellular arrhythmogenic potential in LQT1 is not restricted to cardiomyocytes. NEW & NOTEWORTHY Here, we present the first study of patient-derived LQT1 sympathetic neurons that are norepinephrine secreting, and electrophysiologically functional, in vitro. Our data reveal a novel LQT1 sympathetic neuronal phenotype of increased neurotransmission and excitability. The identified sympathetic neuronal hyperactivity phenotype is of particular relevance as it could contribute to the mechanisms underlying sympathetically triggered arrhythmia in LQT1.

Place, publisher, year, edition, pages
American Physiological Society , 2021. Vol. 321, no 1, p. H217-H227
Keywords [en]
arrhythmia mechanisms, human induced pluripotent stem cells, long QT syndrome, sympathetic hyperactivity, sympathetic neurons
National Category
Neurosciences Cell and Molecular Biology Cardiac and Cardiovascular Systems
Identifiers
URN: urn:nbn:se:umu:diva-187200DOI: 10.1152/ajpheart.01002.2020ISI: 000674982700017PubMedID: 34142889Scopus ID: 2-s2.0-85111137398OAI: oai:DiVA.org:umu-187200DiVA, id: diva2:1591232
Available from: 2021-09-06 Created: 2021-09-06 Last updated: 2022-10-03Bibliographically approved

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Winbo, AnnikaRydberg, Annika

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