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Rapid generation of functional vascular organoids via simultaneous transcription factor activation of endothelial and mural lineages

ABSTRACT: Vascular organoids (VOs) are valuable tools for studying vascular development, disease, and regenerative medicine. However, controlling endothelial and mural compartments independently remains challenging. Here, we present a streamlined method to generate VOs from induced pluripotent stem cells (iPSCs) via orthogonal activation of the transcription factors ETV2 and NKX3.1 using Dox-inducible or modRNA systems. This approach enables efficient co-differentiation of endothelial (iECs) and mural cells (iMCs), producing functional 3D VOs in five days without ECM embedding. VOs matured further upon ECM exposure, forming larger, structured vessels. Single-cell RNA sequencing revealed vascular heterogeneity, and temporal regulation of transcription factor expression allowed modulation of arterial and angiogenic iEC phenotypes. In vivo, VOs engrafted into immunodeficient mice, formed perfused vasculature, and promoted revascularization in models of hind limb ischemia and pancreatic islet transplantation. These findings establish a rapid and versatile VO platform with broad potential for vascular modeling, disease studies, and regenerative cell therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE281002 | GEO | 2025/06/13

REPOSITORIES: GEO

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Project description:Critical limb threatening ischemia (CLTI), the most severe manifestation of peripheral artery disease, results from the chronic blockade of peripheral vessels, usually induced by atherosclerosis. CLTI patients suffer from high risk of amputation of the lower extremities and elevated mortality rates, while they have low options for surgical revascularization due to associated comorbidities. Alternatively, cell-based therapeutic strategies represent an effective and safe approach to promote revascularization and reversal of CLTI. However, the variety in cell types and cell combinations, administration routes or doses applied, have limited their success in clinical trials, being necessary to reach a consensus regarding the optimal “cellular-cocktail” for these patients, prior further application into the clinic. To achieve so, it is essential to understand the mechanisms by which these cells exert their regenerative properties. Herein, we have evaluated and compared, for the first time, the regenerative and vasculogenic potential of endothelial colony forming cells (ECFCs) isolated from either adipose-tissue (AT-ECFCs) or umbilical cord blood (CB-ECFCs), in combination with AT-derived MSCs, in a murine model of CLTI. Furthermore, the long-term molecular changes in CLTI and in response to both combinations have been analyzed in a proteomic quantitative approach. Overall, the administration of AT-MSCs with either AT- or CB-ECFCs, promoted a significant recovery of blood flow in CLTI mice 21 days post-ischemia, which appeared associated to an increased number of vessels in AT treated mice or with wider vessels in CB. Besides, they both modulated the inflammatory and necrotic processes, although the CB group presented the slowest ischemic progression along the assay. Furthermore, many of the protein changes identified are representative of the molecular mechanisms involved in ECFCs and MSCs induced revascularization (immune response, vascular repair, muscle regeneration, etc).

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Rapid generation of functional vascular organoids via simultaneous transcription factor activation of endothelial and mural lineages

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