Engineered cocultures of iPSC-derived atrial cardiomyocytes and atrial fibroblasts for modeling atrial fibrillation

Brown, Grace E.; Han, Yong Duk; Michell, Ashlin R.; Ly, Olivia T.; Vanoye, Carlos G.; Spanghero, Emanuele; George, Alfred L.; Darbar, Dawood; Khetani, Salman R.

doi:10.1126/sciadv.adg1222

Cited by 13 publications

(3 citation statements)

References 77 publications

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“…We also applied cardiac micropatterning and coculture (cMPCC) with atrial fibroblasts to create a comprehensive EMM-cMPCC protocol ( Figure S6 ). 36 Clearly demarcated Z-discs and M-lines are visible in TTN +/+ -hiPSC-aCMs ( Figures 3 N and 3N′), whereas TTN Δ9/Δ9 -hiPSC-aCM organization is diffuse and lacks consistent Z and M-lines ( Figures 3 O and 3O′). TTN Δ9/Δ9 -hiPSC-aCMs demonstrate decreased sarcomeric organization and significantly shortened sarcomere lengths ( Figures 3 P–3T).…”

Section: Resultsmentioning

confidence: 95%

Transient titin-dependent ventricular defects during development lead to adult atrial arrhythmia and impaired contractility

Jiang,

Ly,

Chen

et al. 2024

iScience

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Section: Resultsmentioning

confidence: 95%

Transient titin-dependent ventricular defects during development lead to adult atrial arrhythmia and impaired contractility

Jiang,

Ly,

Chen

et al. 2024

iScience

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“…To address some limitations, we included extensive data from hiPSC-aCM (PC1 knockdown and overexpression) and human samples from patients with AF. The use of hiPSC-aCM in cardiac electrophysiology research is also complicated by the inherent immaturity, however, recent publications have shown hiPSC-aCM recapitulate key aspects of human AF [101][102][103] . To mitigate these concerns, we used state-of-the-art differentiation protocols 42,103 and cross-validated our findings with mouse model samples and the widely used HL-1 cell line.…”

Section: Study Limitationsmentioning

confidence: 99%

Polycystin-1 loss of function increases susceptibility to atrial fibrillation through impaired DNA damage response

Hendrickson,

Abigail Giese,

Fiedler

et al. 2024

Preprint

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Background: The increasing prevalence of atrial fibrillation (AF) and chronic kidney diseases highlights the need for a deeper comprehension of the molecular mechanisms linking them. Mutations in PKD1, the gene encoding Polycystin-1 (PKD1 or PC1), account for 85% of autosomal dominant polycystic kidney disease (ADPKD) cases. This disease often includes cardiac complications such as AF. In cardiomyocytes, PC1 deletion reduces hypertrophic response to pressure overload but promotes baseline ventricular dysfunction, while deletion in fibroblasts ameliorates post-myocardial infarction fibrosis. Despite its known cardiac impact, the role of PC1 in atrial cardiomyocytes and arrhythmias is less understood. Here, we sought to investigate the role of PC1 in AF. Methods: We used intracardiac programmed stimulation and optical mapping to evaluate AF inducibility in two mouse models, Pkd1 R3277C, which recapitulates human ADPKD progression, and cardiomyocyte-specific Pkd1 deletion, and their respective controls. Isolated adult mouse atrial cardiomyocytes, human iPSC-derived atrial cardiomyocytes (hiPSC-aCM), and HL-1 cells served as in vitro cellular models. Molecular mechanisms were evaluated using optical mapping and molecular and biochemical approaches. Results: Loss-of-function PC1 mutations significantly increased AF susceptibility in vivo and facilitated local reentry in ex vivo left atrial appendages. Comprehensive in vitro experiments supported a direct effect of PC1 in atrial cardiomyocytes. PC1-deficient monolayers exhibited increased arrhythmic events, escalating into reentrant spiral waves post-tachypacing. Transcriptomics analysis revealed PC1-dependent regulation of DNA repair, with PC1 deficiency leading to increased DNA damage under stress. PARP1 inhibitors or nicotinamide riboside, which counteract DNA damage-related metabolic consequences, reduced in vitro arrhythmias PC1-deficient monolayers. Overexpression of the C-terminus of PC1 had the opposite effects in DNA repair genes, suggesting its regulatory effects in atrial cardiomyocytes through retinoblastoma/E2F. Analyses of human atrial tissue from non-ADPKD patients showed reduced levels of mature PC1, suggesting a broader relevance of impaired PC1 in AF. Conclusions: Impaired PC1 increases in vivo AF inducibility under programmed electrical stimulation and promotes in vitro arrhythmias in hiPSC-aCM and HL-1 cells. Our findings indicate that PC1 protects against DNA damage to reduce AF susceptibility.

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“…Over the past decade, advances in iPSC differentiation have enabled researchers to generate robust populations of many different cell types. Recent studies have produced reliable protocols for stem cell differentiation to a variety of heart cell types, including ventricular cardiomyocytes [12], [13][14][15][16][17][18], atrial cardiomyocytes [16,19], epicardial cells [9,[20][21][22], cardiac endothelial cells [23,24], cardiac fibroblasts [25][26][27], and nodal cells. [28][29][30] These iPSC-derived cells can be used to model human heart cell behavior and wound repair processes.…”

Section: Introductionmentioning

confidence: 99%

Engineered Cardiac Microtissue Biomanufacturing Using Human Induced Pluripotent Stem Cell Derived Epicardial Cells

Butler,

Ahmed,

Jablonski

et al. 2024

Preprint

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Epicardial cells are a crucial component in constructing in vitro 3D tissue models of the human heart, contributing to the ECM environment and the resident mesenchymal cell population. Studying the human epicardium and its development from the proepicardial organ is difficult, but induced pluripotent stem cells can provide a source of human epicardial cells for developmental modeling and for biomanufacturing heterotypic cardiac tissues. This study shows that a robust population of epicardial cells (approx. 87.7% WT1+) can be obtained by small molecule modulation of the Wnt signaling pathway. The population maintains WT1 expression and characteristic epithelial morphology over successive passaging, but increases in size and decreases in cell number, suggesting a limit to their expandability in vitro. Further, low passage number epicardial cells formed into more robust 3D microtissues compared to their higher passage counterparts, suggesting that the ideal time frame for use of these epicardial cells for tissue engineering and modeling purposes is early on in their differentiated state. Additionally, the differentiated epicardial cells displayed two distinct morphologic sub populations with a subset of larger, more migratory cells which led expansion of the epicardial cells across various extracellular matrix environments. When incorporated into a mixed 3D co-culture with cardiomyocytes, epicardial cells promoted greater remodeling and migration without impairing cardiomyocyte function. This study provides an important characterization of stem cell-derived epicardial cells, identifying key characteristics that influence their ability to fabricate consistent engineered cardiac tissues.

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Engineered cocultures of iPSC-derived atrial cardiomyocytes and atrial fibroblasts for modeling atrial fibrillation

Cited by 13 publications

References 77 publications

Transient titin-dependent ventricular defects during development lead to adult atrial arrhythmia and impaired contractility

Transient titin-dependent ventricular defects during development lead to adult atrial arrhythmia and impaired contractility

Polycystin-1 loss of function increases susceptibility to atrial fibrillation through impaired DNA damage response

Engineered Cardiac Microtissue Biomanufacturing Using Human Induced Pluripotent Stem Cell Derived Epicardial Cells

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