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.
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.
| Original language | English |
|---|---|
| Article number | sxae043 |
| Pages (from-to) | 791–808 |
| Number of pages | 18 |
| Journal | Stem Cells |
| Volume | 42 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - 25 Jul 2024 |
Keywords
- induced pluripotent stem cells; cardiovascular diseases; diabetic vasculopathy; vascular disease modeling; blood vessel organoids; regenerative MEDICINE
