Corrigendum: Phenotypic variability in iPSC-induced cardiomyocytes and cardiac fibroblasts carrying diverse LMNA mutations.

[This corrects the article DOI: 10.3389/fphys.2021.778982.].

Lack of xanthine dehydrogenase leads to a remarkable renal decline in a novel hypouricemic rat model.

Uric acid (UA) is the final metabolite in purine catabolism in humans. Previous studies have shown that the dysregulation of UA homeostasis is detrimental to cardiovascular and kidney health. The Xdh gene encodes for the Xanthine Oxidoreductase enzyme group, responsible for producing UA. To explore how hypouricemia can lead to kidney damage, we created a rat model with the genetic ablation of the Xdh gene on the Dahl salt-sensitive rat background (SSXdh-/-). SSXdh-/- rats lacked UA and exhibited impairment in growth and survival. This model showed severe kidney injury with increased interstitial fibrosis, glomerular damage, crystal formation, and an inability to control electrolyte balance. Using a multi-omics approach, we highlighted that lack of Xdh leads to increased oxidative stress, renal cell proliferation, and inflammation. Our data reveal that the absence of Xdh leads to kidney damage and functional decline by the accumulation of purine metabolites in the kidney and increased oxidative stress.

Generation of a heterozygous FLNC mutation-carrying human iPSC line, USFi002-A, for modeling dilated cardiomyopathy.

Dilated Cardiomyopathy (DCM) is one of the main causes of sudden cardiac death and heart failure and is the leading indication for cardiac transplantation worldwide. Mutations in different genes including TTN, MYH7, and LMNA, have been linked to the development of DCM. Here, we generated a human induced pluripotent stem cell (IPSC) line from a DCM patient with a familial history that carries a frameshift mutation in Filamin C (FLNC). The IPSCs show typical morphology of pluripotent cells, expression of pluripotency markers, normal karyotype, and in vitro capacity to differentiate into all three germ layers.

Establishment of an arrhythmogenic right ventricular cardiomyopathy derived iPSC cell line (USFi004-A) carrying a heterozygous mutation in PKP2 (c.1799delA).

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an autosomal dominant inherited disease, with variable penetrance and expressivity. Currently, more than 14 different genetic loci have been reported for ARVC, the majority being desmosomal genes like Plakophilin-2 (PKP2). Here, we generated an iPSC cell line bearing a pathogenic heterozygous mutation in PKP2 (c.1799delA) from a patient affected by ARVC. Peripheral blood mononuclear cells were reprogrammed by Sendai virus vectors encoding KOS, KLF4, and c-MYC. Derived iPSCs expressed pluripotent markers, showed intact karyotype and demonstrated the ability to differentiate into three germ layers.

Generation of an iPSC cell line (USFi003-A) from a patient with dilated cardiomyopathy carrying a heterozygous mutation in LMNA (p.R541C).

Mutations in the gene that encodes the nuclear envelope proteins lamin A/C (LMNA) are considered to be a prominent cause of Dilated cardiomyopathy (DCM), a leading cause of heart failure and a prevalent indication for heart transplant. Here we described the generation of induced pluripotent stem cells (iPSCs) from a 53-year-old female with DCM plus progressive conduction disease who carry a heterozygous mutation in LMNA (c.1621C > T, p.R541C). PBMCs isolated from the patient were reprogrammed with Yamanaka factors KOS, KLF4, and c-MYC by the non-integrating sendai virus vector system. The obtained iPSC lines demonstrated normal karyotype and pluripotent identity.

Phenotypic Variability in iPSC-Induced Cardiomyocytes and Cardiac Fibroblasts Carrying Diverse LMNA Mutations.

Mutations in the LMNA gene (encoding lamin A/C) are a significant cause of familial arrhythmogenic cardiomyopathy. Although the penetrance is high, there is considerable phenotypic variability in disease onset, rate of progression, arrhythmias, and severity of myopathy. To begin to address whether this variability stems from specific LMNA mutation sites and types, we generated seven patient-specific induced pluripotent stem cell (iPSC) lines with various LMNA mutations. IPSC-derived cardiomyocytes (iCMs) and cardiac fibroblasts (iCFs) were differentiated from each line for phenotypic analyses. LMNA expression and extracellular signal-regulated kinase pathway activation were perturbed to differing degrees in both iCMs and iCFs from the different lines. Enhanced apoptosis was observed in iCMs but not in iCFs. Markedly diverse irregularities of nuclear membrane morphology were present in iCFs but not iCMs, while iCMs demonstrated variable sarcomere disarray. Heterogenous electrophysiological aberrations assayed by calcium indicator imaging and multi-electrode array suggest differing substrates for arrhythmia that were accompanied by variable ion channel gene expression in the iCMs. Coculture studies suggest enhancement of the LMNA mutation effects on electrophysiological function exerted by iCFs. This study supports the utility of patient-specific iPSC experimental platform in the exploration of mechanistic and phenotypic heterogeneity of different mutations within a cardiac disease-associated gene. The addition of genetically defined coculture of cardiac-constituent non-myocytes further expands the capabilities of this approach.