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RNA-sequencing of endothelial cells and 3D cardiac microtissues from hiPSCs

ABSTRACT: We previously showed that two major cellular components of the human heart, cardiac endothelial cells and cardiomyocytes, could be derived simultaneously from human induced pluripotent stem cells (hiPSCs). In vivo studies in mice have shown these lineages derive from a common MESP1+ mesoderm progenitor. Although this has been investigated using whole transcriptome sequencing, the transcriptional control and dynamics of their segregation from cardiac mesoderm are not yet fully understood. In addition, the same transgenic approach cannot be used in human. Here, we used bulk and single cell RNA sequencing (RNAseq) to investigate EC and cardiomyocytes co-differentiation in hiPSC. We confirmed segregation of these two cardiac lineages from common cardiac mesoderm precursors but more importantly, revealed a critical role of transient expression of the transcription factor ETV2 for endothelial fate specification and showed unexpectedly that functional cardiomyocytes could also originate from ETV2+ progenitors. This dataset contain 10X-based scRNA-seq data human induced pluripotent stem cell derived endothelial cells and 3D cardac microtissues, as well as bulk RNA-seq data of endothelial cells derived from cardiac and paraxial mesoderm.

ORGANISM(S): Homo sapiens

PROVIDER: GSE151427 | GEO | 2025/08/20

REPOSITORIES: GEO

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			Action	DRS
		Other
	GSE151427_RAW.tar	Raw
	GSE151427_RPKM_normalized_CMEC_PMEC_bulk.csv.gz	Csv
	GSE151427_RPKM_normalized_VASAseq.csv.gz	Csv
	GSE151427_samplesheet_VASAseq.csv.gz	Csv

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Project description:The first macrophages that seed the developing heart originate from the yolk sac during fetal life. While murine studies reveal important homeostatic and reparative functions in adults, we know little about their roles in the earliest stages of human heart development due to a lack of accessible tissue. Generation of bioengineered human cardiac microtissues from pluripotent stem cells models these first steps in cardiac tissue development, however macrophages have not been included in these studies. To bridge these gaps, we differentiated human embryonic stem cells (hESCs) into primitive LYVE1+ macrophages (hESC-macrophages; akin to yolk sac macrophages) that stably engrafted within cardiac microtissues composed of hESC-cardiomyocytes and fibroblasts to study reciprocal interactions. Engraftment induced a tissue resident macrophage gene program resembling human fetal cardiac macrophages, enriched in efferocytic pathways. Functionally, hESC-macrophages induced production and maturation of cardiomyocyte sarcomeric proteins, and enhanced contractile force, relaxation kinetics, and electrical properties. Mechanistically, the primary effect of hESC-macrophages was during the stressful events surrounding early microtissue formation, where they engaged in phosphatidylserine dependent ingestion of apoptotic cardiomyocyte cargo, which reinforced core resident macrophage identity, reduced microtissue stress and drove hESC-cardiomyocytes to become more similar to human ventricular cardiomyocytes found in early development, both transcriptionally and metabolically. Inhibiting efferocytosis of hESC-cardiomyocytes by hESC-macrophages led to increased cell stress, impaired sarcomeric protein maturation and reduced cardiac microtissue function (contraction and relaxation). Taken together, macrophage-engineered human cardiac microtissues represent a considerably improved model for human heart development, and reveal a major beneficial, yet previously unappreciated role for human primitive macrophages in enhancing cardiac tissue function.

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RNA-sequencing of endothelial cells and 3D cardiac microtissues from hiPSCs

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