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Transcriptomic analysis of different human cardiac cell types produced in vitro from human pluripotent stem cells or derived from patients.

ABSTRACT: The epicardium, an epithelium covering the heart, is essential for cardiac development. During embryogenesis, the epicardium provides instructive signals for the growth and maturation of cardiomyocytes and for coronary angiogenesis. We generated an in vitro model of human embryonic epicardium derived from human pluripotent stem cells (hPSC-epi). These cells were able to differentiate into cardiac fibroblasts (cf) and smooth muscle cells (smc) in vitro (hPSC-epi-cf and hPSC-epi-smc respectively). Furthermore, we showed that they improved maturation of hPSC-derived cardiomyocytes (hPSC-cardio) in vitro while neural crest cells derived from hPSC (hPSC-NC) could not. Furthermore, they improved survival of hPSC-cardio and stimulated angiogenesis when injected in a rat model of myocardium infarction. We performed mRNA sequencing of the hPSC-epi, hPSC-epi-cf, hPSC-smc and hPSC-NC in order to identify the secreted molecules specifically produced by the hPSC-epi and/or its derivatives in comparison with the hPSC-NC. Vascular smooth muscle cells have different embryonic origins and different properties depending on their location in the body. The coronary smooth muscle cells come from the epicardium while the aortic ones come from the mesoderm or the neural crest. We performed mRNA sequencing of human coronary artery smc and human aortic smc to identify a specific signature of the coronary smc. We also compared the genes expressed in the hPSC-epi-smc and the smc derived from hPSC-derived lateral plate mesoderm.

ORGANISM(S): Homo sapiens

PROVIDER: GSE122714 | GEO | 2019/05/13

REPOSITORIES: GEO

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Project description:Aryl-hydrocarbon receptor protects against endochondral ossification of modulated smooth muscle cells in atherosclerosis Introduction: Smooth muscle cells (SMC) play a critical role in atherosclerosis. The Aryl hydrocarbon receptor (AHR) is an environment-sensing transcription factor that contributes to vascular development, and has been implicated in coronary artery disease (CAD) risk. We hypothesized that AHR can affect atherosclerosis by regulating phenotypic modulation of SMC. Methods: We combined RNA-Seq, ChIP-Seq, ATAC-Seq and in-vitro assays in human coronary artery SMC (HCASMC), with single-cell RNA-Seq (scRNA-Seq), histology, and RNAscope in an SMC-specific lineage-tracing Ahr knockout mouse model of atherosclerosis to better understand the role of AHR in vascular disease. Results: Genomic studies coupled with functional assays in cultured HCASMC revealed that AHR modulates HCASMC phenotype and suppresses ossification in these cells. Lineage tracing and activity tracing studies in the mouse aortic sinus showed that the Ahr pathway is active in modulated SMC in the atherosclerotic lesion cap. Furthermore, scRNA-Seq studies of the SMC-specific Ahr knockout mice showed a significant increase in the proportion of modulated SMC expressing chondrocyte markers such as Col2a1 and Alpl, which localized to the lesion neointima. These cells, which we term chondromyocytes (CMC), were also identified in the neointima of human coronary arteries. In histological analyses, these changes manifested as larger lesion size, increased lineage-traced SMC participation in the lesion, decreased lineage-traced SMC in the lesion cap, and increased alkaline phosphatase activity in lesions in the Ahr knockout compared to wild-type mice. We propose that AHR is likely protective based on these data and inference from human genetic analyses. Conclusion: Overall, we conclude that AHR promotes maintenance of lesion cap integrity and diminishes the disease related SMC-to-CMC transition in atherosclerotic tissues.

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Transcriptomic analysis of different human cardiac cell types produced in vitro from human pluripotent stem cells or derived from patients.

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