CD151 expression indicates the subtype specification of human induced pluripotent stem cell-derived atrial and ventricular cardiomyocytes
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE179769 | GEO | 2024/01/29
REPOSITORIES: GEO
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Project description:Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia treatable with antiarrhythmic drugs, but patient responses are highly variable. Human induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-aCMs) are useful for discovering precision therapeutics, but current platforms yield an immature cellular phenotype and are not easily scalable for high-throughput screening. Here, we report that primary adult atrial, but not ventricular, fibroblasts induced greater functional iPSC-aCM maturation, partly through connexin-40 and ephrin-B1 signaling. We developed a protein patterning process within industry-standard multiwell plates to engineer patterned co-culture (PC) of iPSC-aCMs and atrial fibroblasts that significantly enhanced iPSC-aCM structural, electrical, contractile, and metabolic maturation for 6+ weeks versus conventional mono-/co-cultures. PC displayed greater sensitivity for detecting drug efficacy than monocultures, and enabled the modeling and pharmacological or gene editing treatment of an AF-like electrophysiological phenotype due to a sodium channel mutation. In conclusion, PC is useful to elucidate heterotypic cell signaling in the atria, drug screening, and to model AF.
2024-01-19 | GSE239321 | GEO
Project description:Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia treatable with antiarrhythmic drugs, but patient responses are highly variable. Human induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-aCMs) are useful for discovering precision therapeutics, but current platforms yield an immature cellular phenotype and are not easily scalable for high-throughput screening. Here, we report that primary adult atrial, but not ventricular, fibroblasts induced greater functional iPSC-aCM maturation, partly through connexin-40 and ephrin-B1 signaling. We developed a protein patterning process within industry-standard multiwell plates to engineer patterned co-culture (PC) of iPSC-aCMs and atrial fibroblasts that significantly enhanced iPSC-aCM structural, electrical, contractile, and metabolic maturation for 6+ weeks versus conventional mono-/co-cultures. PC displayed greater sensitivity for detecting drug efficacy than monocultures, and enabled the modeling and pharmacological or gene editing treatment of an AF-like electrophysiological phenotype due to a sodium channel mutation. In conclusion, PC is useful to elucidate heterotypic cell signaling in the atria, drug screening, and to model AF.
2024-01-19 | GSE239317 | GEO
Project description:Atrial fibrillation (AF) has an estimated prevalence of 1.5–2%, making it the most common cardiac arrhythmia. The mechanisms that cause and sustain AF are still not completely understood. An association between AF and systemic as well as local inflammatory processes has been reported, however, the exact mechanisms underlying this association have not been established. While it is understood that tissue resident macrophages can influence cardiac electrophysiology, the effects of activated pro-inflammatory macrophages have not been described yet. This study investigated the pro-arrhythmic effects of activated macrophages (M1) on human induced pluripotent stem cell (hiPSC)-derived atrial cardiomyocytes (aCM), to propose a mechanistic link between inflammation and AF. Two hiPSC lines from healthy individuals were differentiated to aCMs and M1 macrophages. Electrophysiology characteristics of M1 and aCM cocultures were analysed for beat rate irregularity, electrogram amplitude and conduction velocity. M1 cocultures resulted in a significant increase in beat rate irregularity and decrease in electrogram amplitude compared to other conditions tested, including aCMs treated with activated M1 supernatant, which did not produce an increase in irregularity. Conduction analysis further showed significantly lower conduction homogeneity in M1 cocultures. Immunosuppression through glucocorticoids significantly decreased beat irregularity in aCM+M1 cocultures compared to vehicle. RNA sequencing performed in aCMs, revealed downregulation of various ion channels (SCNA5, KCNA5, ATP1A1), as a result of the M1 coculture. Electrophysiology related transcription changes were reversed by glucocorticoid treatment. This study establishes a causal relationship between M1 activation and the development of subsequent atrial arrhythmia, documented as irregularity in spontaneous electrical activation in aCM cocultured with activated macrophages. Further, beat rate irregularity could be alleviated using anti-inflammatory steroidal glucocorticoids. These results strongly support the relevance of the proposed hiPSC-derived coculture model and point at macrophage mediated inflammation as a potential AF mechanism.
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Project description:Here, we targeted mCherry to the COUP-TFII genomic locus in NKX2.5eGFP/+ hPSCs. Upon differentiation to atrial and ventricular cardiomyocytes (CMs) this dual atrial COUP-TFIImCherry/+-NKX2.5eGFP/+ reporter line allowed identification and selection of GFP+ (G+)/mCherry+ (M+) CMs following cardiac differentiation. These cells exhibited transcriptional and functional properties of atrial CMs, whereas G+/M- CMs displayed ventricular characteristics. Via CRISPR/Cas9-mediated knockout, we demonstrated that COUP-TFII is not required atrial specification in hPSCs.
2017-12-31 | GSE100199 | GEO
Project description:Atrial fibrillation (AF), the most common arrhythmia, is occasionally associated with cardiac developmental defects, but causal relationships are poorly defined. Importantly, functional compensation for developmental defects may mask increased risk of arrhythmia in adults. Here, we deleted 9 amino acids (Δ9) within a highly conserved A-band region of titin, a giant protein that serves as a molecular spring in cardiomyocytes, in both zebrafish and human induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCMs). We find that the cardiac morphology of ttnaΔ9/Δ9 homozygous zebrafish embryos is perturbed and accompanied by reduced functional output, but ventricular function recovers within a few days of embryonic development, with most embryos reaching adulthood. Despite normal ventricular function, ttnaΔ9/Δ9 adults exhibit AF and atrial cardiomyopathy, with a striking absence of fibrosis, and these findings are recapitulated in TTNΔ9/Δ9-hiPSC-aCMs. Electrophysiological and proteomics analyses reveal atrial action potential shortening and increased expression and function of the cardiac potassium channel Kv7.1 and the slow delayed rectifier potassium current (IKs). Pharmacological suppression of IKs in both models prevents AF and improves atrial contractility. Collectively, these findings reveal how a small internal deletion in a large structural protein causes developmental abnormalities that functionally recover but increase the risk of adult cardiac disease via ion channel remodeling. The observed rescue with targeted antiarrhythmic therapy may have broader implications for the treatment of patients who harbor disease-causing rare variants in sarcomeric proteins.
2024-08-09 | PXD038300 | Pride
Project description:Understanding how the atrial and ventricular chambers of the heart maintain their distinct identity is a prerequisite for treating chamber-specific diseases. Here, we selectively inactivated the transcription factor Tbx5 in the atrial working myocardium of the neonatal mouse heart to show that it is required to maintain atrial identity. Atrial Tbx5 inactivation downregulated highly chamber specific genes such as Myl7 and Nppa, and conversely, increased the expression of ventricular identity genes including Myl2. Using combined single nucleus transcriptome and open chromatin profiling, we assessed genomic accessibility changes underlying the altered atrial identity expression program, identifying 1846 genomic loci with greater accessibility in control atrial cardiomyocytes compared to KO aCMs. 69% of the control-enriched ATAC regions were bound by TBX5, demonstrating a role for TBX5 in maintaining atrial genomic accessibility. These regions were associated with genes that had higher expression in control aCMs compared to KO aCMs, suggesting they act as TBX5-dependent enhancers. We tested this hypothesis by analyzing enhancer chromatin looping using HiChIP and found 510 chromatin loops that were sensitive to TBX5 dosage. Of the loops enriched in control aCMs, 74.8% contained anchors in control-enriched ATAC regions. Together, these data demonstrate a genomic role for TBX5 in maintaining the atrial gene expression program by binding to atrial enhancers and preserving tissue-specific chromatin architecture of atrial enhancers.
2023-08-11 | GSE237090 | GEO
Project description:Understanding how the atrial and ventricular chambers of the heart maintain their distinct identity is a prerequisite for treating chamber-specific diseases. Here, we selectively inactivated the transcription factor Tbx5 in the atrial working myocardium of the neonatal mouse heart to show that it is required to maintain atrial identity. Atrial Tbx5 inactivation downregulated highly chamber specific genes such as Myl7 and Nppa, and increased expression of ventricular identity genes including Myl2. Using combined single nucleus transcriptome and open chromatin profiling, we assessed genomic accessibility changes underlying the altered atrial identity expression program, identifying 1846 genomic loci with greater accessibility in control atrial cardiomyocytes compared to KO aCMs. 69% of the control-enriched ATAC regions were bound by TBX5, demonstrating a role for TBX5 in maintaining genomic accessibility. These regions were associated with genes that had higher expression in control aCMs compared to KO aCMs, suggesting they act as TBX5-dependent enhancers. To confirm this hypothesis we analyzed chromatin looping of enhancers marked by H3K27Ac using HiChIP and found 510 chromatin loops that were sensitive to TBX5 dosage. Of the loops enriched in control aCMs, 73.7% contained anchors in control-enriched ATAC regions. Conversely, Tbx5 overexpression in the ventricular myocardium drove atrial gene expression. Together, these data demonstrate a role for TBX5 in maintaining the atrial gene expression program by binding to atrial enhancers to preserve tissue-specific chromatin architecture. We highlight this phenomenon at major atrial identity genes including Nppa, Bmp10 and Myl7.
2023-08-11 | GSE222579 | GEO
Project description:Understanding how the atrial and ventricular chambers of the heart maintain their distinct identity is a prerequisite for treating chamber-specific diseases. Here, we selectively inactivated the transcription factor Tbx5 in the atrial working myocardium of the neonatal mouse heart to show that it is required to maintain atrial identity. Atrial Tbx5 inactivation downregulated highly chamber specific genes such as Myl7 and Nppa, and increased expression of ventricular identity genes including Myl2. Using combined single nucleus transcriptome and open chromatin profiling, we assessed genomic accessibility changes underlying the altered atrial identity expression program, identifying 1846 genomic loci with greater accessibility in control atrial cardiomyocytes compared to KO aCMs. 69% of the control-enriched ATAC regions were bound by TBX5, demonstrating a role for TBX5 in maintaining genomic accessibility. These regions were associated with genes that had higher expression in control aCMs compared to KO aCMs, suggesting they act as TBX5-dependent enhancers. To confirm this hypothesis we analyzed chromatin looping of enhancers marked by H3K27Ac using HiChIP and found 510 chromatin loops that were sensitive to TBX5 dosage. Of the loops enriched in control aCMs, 73.7% contained anchors in control-enriched ATAC regions. Conversely, Tbx5 overexpression in the ventricular myocardium drove atrial gene expression. Together, these data demonstrate a role for TBX5 in maintaining the atrial gene expression program by binding to atrial enhancers to preserve tissue-specific chromatin architecture. We highlight this phenomenon at major atrial identity genes including Nppa, Bmp10 and Myl7.
2023-08-11 | GSE222373 | GEO
Project description:Atrial fibrillation (AF) is the most common sustained arrhythmia in humans, yet the molecular basis of AF remains incompletely understood. To determine the cell type-specific transcriptional changes underlying AF, we performed single-nucleus RNA-seq (snRNA-seq) on age- and sex-matched left atrial (LA) samples from 18 patients with AF and 16 controls without AF. From more than 175,000 nuclei we identified 15 cell types but found that only cardiomyocytes (CMs) and macrophages (MΦs) had a significant number of differentially expressed genes in patients with AF. Attractin Like 1 (ATRNL1) was strongly overexpressed in CMs among patients with AF and localized to the intercalated discs. Further, in both knockdown and overexpression experiments in atrial human embryonic stem cell-derived CMs (hESC-aCMs) we identified a potent role for ATRNL1 in cell stress response, cardiac conduction, cell junction organization and in modulation of the cardiac action potential. Finally, we prioritized genes at the known genetic loci for AF and identified an unexpected expression for a leading AF candidate gene, KCNN3. In sum, we have identified a role for ATRNL1 and other differentially regulated genes that may serve as potential therapeutic targets for this common arrhythmia.
2024-09-24 | GSE255612 | GEO
Project description:Atrial fibrillation (AF) is the most common sustained arrhythmia in humans, yet the molecular basis of AF remains incompletely understood. To determine the cell type-specific transcriptional changes underlying AF, we performed single-nucleus RNA-seq (snRNA-seq) on age- and sex-matched left atrial (LA) samples from 18 patients with AF and 16 controls without AF. From more than 175,000 nuclei we identified 15 cell types but found that only cardiomyocytes (CMs) and macrophages (MΦs) had a significant number of differentially expressed genes in patients with AF. Attractin Like 1 (ATRNL1) was strongly overexpressed in CMs among patients with AF and localized to the intercalated discs. Further, in both knockdown and overexpression experiments in atrial human embryonic stem cell-derived CMs (hESC-aCMs) we identified a potent role for ATRNL1 in cell stress response, cardiac conduction, cell junction organization and in modulation of the cardiac action potential. Finally, we prioritized genes at the known genetic loci for AF and identified an unexpected expression for a leading AF candidate gene, KCNN3. In sum, we have identified a role for ATRNL1 and other differentially regulated genes that may serve as potential therapeutic targets for this common arrhythmia.
2024-09-24 | GSE255991 | GEO