Unveiling impaired vascular function and cellular heterogeneity in diabetic donor-derived vascular organoids

Naderi-Meshkin, Hojjat and Wahyu Setyaningsih, Wiwit A. and Yacoub, Andrew and Carney, Garrett and Cornelius, Victoria A. and Nelson, Clare-Ann and Kelaini, Sophia and Donaghy, Clare and Dunne, Philip D. and Amirkhah, Raheleh and Zampetaki, Anna and Zeng, Lingfang and Stitt, Alan W. and Lois, Noemi and Grieve, David J. and Margariti, Andriana (2024) Unveiling impaired vascular function and cellular heterogeneity in diabetic donor-derived vascular organoids. Stem Cells, 42 (9). pp. 791-808. ISSN 10665099

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Abstract

Vascular organoids (VOs), derived from induced pluripotent stem cells (iPSCs), hold promise as in vitro disease models and drug screening platforms. However, their ability to faithfully recapitulate human vascular disease and cellular composition remains unclear. In this study, we demonstrate that VOs derived from iPSCs of donors with diabetes (DB-VOs) exhibit impaired vascular function compared to non-diabetic VOs (ND-VOs). DB-VOs display elevated levels of reactive oxygen species (ROS), heightened mitochondrial content and activity, increased proinflammatory cytokines, and reduced blood perfusion recovery in vivo. Through comprehensive single-cell RNA sequencing, we uncover molecular and functional differences, as well as signaling networks, between vascular cell types and clusters within DB-VOs. Our analysis identifies major vascular cell types (endothelial cells ECs, pericytes, and vascular smooth muscle cells) within VOs, highlighting the dichotomy between ECs and mural cells. We also demonstrate the potential need for additional inductions using organ-specific differentiation factors to promote organ-specific identity in VOs. Furthermore, we observe basal heterogeneity within VOs and significant differences between DB-VOs and ND-VOs. Notably, we identify a subpopulation of ECs specific to DB-VOs, showing overrepresentation in the ROS pathway and underrepresentation in the angiogenesis hallmark, indicating signs of aberrant angiogenesis in diabetes. Our findings underscore the potential of VOs for modeling diabetic vasculopathy, emphasize the importance of investigating cellular heterogeneity within VOs for disease modeling and drug discovery, and provide evidence of GAP43 (neuromodulin) expression in ECs, particularly in DB-VOs, with implications for vascular development and disease. © 2024 The Author(s). Published by Oxford University Press.

Item Type: Article
Additional Information: Cited by: 3; All Open Access, Hybrid Gold Open Access
Uncontrolled Keywords: Animals; Cell Differentiation; Diabetes Mellitus; Endothelial Cells; Humans; Induced Pluripotent Stem Cells; Mice; Organoids; Reactive Oxygen Species; cytokine; reactive oxygen metabolite; reactive oxygen metabolite; angiogenesis; animal experiment; Article; cell heterogeneity; cell subpopulation; controlled study; diabetes mellitus; donor; endothelium cell; human; human cell; in vivo study; induced pluripotent stem cell; male; mouse; nonhuman; organoid; perfusion; pericyte; perivascular cell; signal transduction; single cell RNA seq; vascular disease; vascular smooth muscle cell; animal; cell differentiation; diabetes mellitus; induced pluripotent stem cell; metabolism; pathology
Subjects: R Medicine > RN Non Surgical Divisions
Divisions: Faculty of Medicine, Public Health and Nursing > Non Surgical Divisions
Depositing User: Ani PURWANDARI
Date Deposited: 16 Apr 2025 07:38
Last Modified: 16 Apr 2025 07:38
URI: https://ir.lib.ugm.ac.id/id/eprint/16105

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