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Organoid Culture Induces an Activated Pro-angiogenic Phenotype in Human Pericytes: Implications for Ascending Thoracic Aortic Aneurysm Pathophysiology

ABSTRACT: Pericytes serve critical roles including stabilization of neovessels during vasculogenesis and angiogenesis. In larger blood vessels such as the aorta, pericytes are associated with the vasa vasorum, a microvascular network within the outer layer of the adventitia. Using pericytes from both normal and aneurysmal human aorta, this study sought to determine the influence of spheroid culture conditions on aortic vasa vasorum-associated pericyte phenotype and function. Here, we reveal the remarkable plasticity of pericytes as three-dimensional spheroid-based culture of human aorta-derived pericytes, which yields an organoid that promotes pro-angiogenic pathways. The marker profile of pericyte-generated organoids serves as an inducible and importantly, reversible phenotypic signature of pericyte activation. Pericytes from human aneurysm exhibit diminished pro-angiogenic activation and persist in a quiescent, hypercontractile state in organoid culture, thus pointing to a potential to uncover new pathophysiology of human aortic disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE276276 | GEO | 2025/12/31

REPOSITORIES: GEO

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Project description:Pericytes have been implicated in regulation of inflammatory, reparative, fibrogenic and angiogenic responses in several different organs and pathologic conditions. Although the adult mammalian heart contains abundant pericytes, their fate and involvement in myocardial disease remains unknown. We used NG2Dsred;PDGFRaEGFP pericyte-fibroblast dual reporter mice and inducible NG2CreER mice to study the fate and phenotypic modulation of pericytes in a model of myocardial infarction. The transcriptomic profile of pericyte-derived fibroblasts was studied using PCR arrays. The transcriptomic profile of NG2 lineage cells (pericytes) was studied in control and infarcted hearts using single cell RNA-sequencing analysis. The role of TGF-b signaling in regulation of pericyte phenotype in vivo was investigated using pericyte-specific Tgfbr2 knockout mice. In vitro, the effects of TGF-b were studied in cultured human placental pericytes.In normal mouse hearts, NG2 and PDGFRa identified distinct non-overlapping populations of pericytes and fibroblasts respectively. Following myocardial infarction, a population of cells expressing both pericyte and fibroblast markers emerged. These cells expressed large amounts of extracellular matrix (ECM) genes. Lineage tracing demonstrated that in the infarcted region, a subpopulation of pericytes underwent fibroblast conversion. Single cell RNA-seq experiments demonstrated expansion and diversification of pericyte-derived cells in the infarct, associated with emergence of subpopulations exhibiting accentuated matrix gene synthesis. In vitro studies and the profile of pericyte-derived fibroblasts identified TGF-b as a potentially causative mediator in fibrogenic activation of infarct pericytes. However, pericyte-specific Tgfbr2 disruption had no significant effects on myofibroblast infiltration and collagen deposition in the infarct. Pericyte-specific TGF-b signaling was involved in vascular maturation, mediating formation of a mural cell coat investing infarct neovessels. These reparative effects of infarct pericytes protected the infarcted heart from dilative remodeling.

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Organoid Culture Induces an Activated Pro-angiogenic Phenotype in Human Pericytes: Implications for Ascending Thoracic Aortic Aneurysm Pathophysiology

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