Precise Modulation of the Retinoic Acid/CYP26A1 Axis Enables Reproducible Differentiation of Atrial-like Cardiomyocytes
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PROVIDER: PRJNA698345 | ENA |
REPOSITORIES: ENA
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Project description:Vitamin A/Retinoic Acid (RA) signaling is essential for heart development. In cardiac progenitor cells (CPCs), RA signaling induces the expression of atrial lineage genes while repressing ventricular genes, thereby promoting the acquisition of an atrial cardiomyocyte cell fate. To achieve this, RA coordinates a complex regulatory network of downstream effectors that is not fully identified. To address this gap, we applied a functional genomics approach (scRNAseq, scATACseq and ChIP-seq) to untreated and RA-treated human embryonic stem cells (hESCs)-derived CPCs. Unbiased analysis revealed that the Hippo effectors YAP and TEAD4 are integrated with the atrial transcription factor enhancer network, and that YAP1 is necessary for activation of RA-enhancers in CPCs. Furthermore, scRNAseq analysis of control and conditionally YAP KO mouse E7.75 embryos (Sox2cre) revealed that the expression of atrial lineage genes such as NR2F2 is compromised by YAP deletion in the CPCs of the second heart field. Accordingly, we found that YAP is required for the formation of an atrial chamber but is dispensable for the formation of a ventricle, in hESC-derived patterned cardiac organoids. Overall, our findings revealed that YAP1 is a non-canonical effector of RA signaling essential for the acquisition of atrial lineages during cardiogenesis.
2025-05-10 | GSE270962 | GEO
Project description:Vitamin A/Retinoic Acid (Vit A/RA) signaling is essential for heart development. In cardiac progenitor cells (CPCs), RA signaling induces the expression of atrial lineage genes while repressing ventricular genes, thereby promoting the acquisition of an atrial cardiomyocyte cell fate. To achieve this, RA coordinates a complex regulatory network of downstream effectors that is not fully identified. To address this gap, we applied a functional genomics approach (scRNAseq, scATACseq and ChIP-seq) to untreated and RA-treated human embryonic stem cells (hESCs)-derived CPCs. Unbiased analysis revealed that the Hippo effectors YAP and TEAD4 are integrated with the atrial transcription factor enhancer network, and that YAP1 is necessary for activation of RA-enhancers in CPCs. Furthermore, scRNAseq analysis of control and conditionally YAP KO mouse E7.75 embryos (Sox2cre) revealed that the expression of atrial lineage genes such as NR2F2 is compromised by YAP deletion in the CPCs of the second heart field. Accordingly, we found that YAP is required for the formation of an atrial chamber but is dispensable for the formation of a ventricle, in hESC-derived patterned cardiac organoids. Overall, our findings revealed that YAP1 is a non-canonical effector of RA signaling essential for the acquisition of atrial lineages during cardiogenesis.
2025-05-10 | GSE271216 | GEO
Project description:Vitamin A/Retinoic Acid (Vit A/RA) signaling is essential for heart development. In cardiac progenitor cells (CPCs), RA signaling induces the expression of atrial lineage genes while repressing ventricular genes, thereby promoting the acquisition of an atrial cardiomyocyte cell fate. To achieve this, RA coordinates a complex regulatory network of downstream effectors that is not fully identified. To address this gap, we applied a functional genomics approach (scRNAseq, scATACseq and ChIP-seq) to untreated and RA-treated human embryonic stem cells (hESCs)-derived CPCs. Unbiased analysis revealed that the Hippo effectors YAP and TEAD4 are integrated with the atrial transcription factor enhancer network, and that YAP1 is necessary for activation of RA-enhancers in CPCs. Furthermore, scRNAseq analysis of control and conditionally YAP KO mouse E7.75 embryos (Sox2cre) revealed that the expression of atrial lineage genes such as NR2F2 is compromised by YAP deletion in the CPCs of the second heart field. Accordingly, we found that YAP is required for the formation of an atrial chamber but is dispensable for the formation of a ventricle, in hESC-derived patterned cardiac organoids. Overall, our findings revealed that YAP1 is a non-canonical effector of RA signaling essential for the acquisition of atrial lineages during cardiogenesis.
2025-05-10 | GSE271214 | GEO
Project description:Vitamin A/Retinoic Acid (Vit A/RA) signaling is essential for heart development. In cardiac progenitor cells (CPCs), RA signaling induces the expression of atrial lineage genes while repressing ventricular genes, thereby promoting the acquisition of an atrial cardiomyocyte cell fate. To achieve this, RA coordinates a complex regulatory network of downstream effectors that is not fully identified. To address this gap, we applied a functional genomics approach (scRNAseq, scATACseq and ChIP-seq) to untreated and RA-treated human embryonic stem cells (hESCs)-derived CPCs. Unbiased analysis revealed that the Hippo effectors YAP and TEAD4 are integrated with the atrial transcription factor enhancer network, and that YAP1 is necessary for activation of RA-enhancers in CPCs. Furthermore, scRNAseq analysis of control and conditionally YAP KO mouse E7.75 embryos (Sox2cre) revealed that the expression of atrial lineage genes such as NR2F2 is compromised by YAP deletion in the CPCs of the second heart field. Accordingly, we found that YAP is required for the formation of an atrial chamber but is dispensable for the formation of a ventricle, in hESC-derived patterned cardiac organoids. Overall, our findings revealed that YAP1 is a non-canonical effector of RA signaling essential for the acquisition of atrial lineages during cardiogenesis.
2025-05-10 | GSE271213 | GEO
Project description:Induction of the specific retinoic acid receptor alpha (RARα) increased the efficiency of atrial differentiation to 72% compared with 45% after odulating the retinoic acid (RA) pathway with all-trans RA (atRA). For further purification of the AMs, we describe a metabolic selection procedure that enhanced the AM percentage to more than 90% without compromising the AM yield (15,542 per EB, equal to 3.11 per hPSC) or functionality of the AMs as evaluated by RNAseq, immunostaining, and optical action potential measurement.
2022-04-15 | GSE200662 | GEO
Project description:A Retinoic Acid:YAP1 signaling axis controls atrial lineage commitment
| PRJNA1130520 | ENA
Project description:A Retinoic Acid:YAP1 signaling axis controls atrial lineage commitment
| PRJNA1129119 | ENA
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) 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:A Retinoic Acid:YAP1 signaling axis controls atrial lineage commitment [scRNA-seq]
| PRJNA1130467 | ENA