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Unveiling impaired vascular function and cellular heterogeneity in diabetic donor-derived vascular organoids.
Naderi-Meshkin, Hojjat; Wahyu Setyaningsih, Wiwit A; Yacoub, Andrew; Carney, Garrett; Cornelius, Victoria A; Nelson, Clare-Ann; Kelaini, Sophia; Donaghy, Clare; Dunne, Philip D; Amirkhah, Raheleh; Zampetaki, Anna; Zeng, Lingfang; Stitt, Alan W; Lois, Noemi; Grieve, David J; Margariti, Andriana.
Afiliação
  • Naderi-Meshkin H; The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, BT9 7BL, United Kingdom.
  • Wahyu Setyaningsih WA; The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, BT9 7BL, United Kingdom.
  • Yacoub A; Department of Anatomy, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Sleman, D.I. Yogyakarta, 55281, Indonesia.
  • Carney G; The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, BT9 7BL, United Kingdom.
  • Cornelius VA; The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, BT9 7BL, United Kingdom.
  • Nelson CA; The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, BT9 7BL, United Kingdom.
  • Kelaini S; The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, BT9 7BL, United Kingdom.
  • Donaghy C; The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, BT9 7BL, United Kingdom.
  • Dunne PD; The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, BT9 7BL, United Kingdom.
  • Amirkhah R; The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, BT9 7AE, United Kingdom.
  • Zampetaki A; The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, BT9 7AE, United Kingdom.
  • Zeng L; School of Cardiovascular Medicine and Sciences, BHF Centre of Research Excellence, King's College London, London, SE5 9NU, United Kingdom.
  • Stitt AW; School of Cardiovascular Medicine and Sciences, BHF Centre of Research Excellence, King's College London, London, SE5 9NU, United Kingdom.
  • Lois N; The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, BT9 7BL, United Kingdom.
  • Grieve DJ; The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, BT9 7BL, United Kingdom.
  • Margariti A; The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, BT9 7BL, United Kingdom.
Stem Cells ; 42(9): 791-808, 2024 Sep 10.
Article em En | MEDLINE | ID: mdl-39049437
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Organoides / Células-Tronco Pluripotentes Induzidas Limite: Animals / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Organoides / Células-Tronco Pluripotentes Induzidas Limite: Animals / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article