Impaired Function in Diabetic Patient iPSCs-derived Blood Vessel Organoids Stem from a Subpopulation of Vascular Cells
Impaired Function in Diabetic Patient iPSCs-derived Blood Vessel Organoids Stem from a Subpopulation of Vascular Cells
复制标题
DOI：
10.1101/2022.07.18.500478
复制
发表时间：
2022-07
期刊：
影响因子：
--
通讯作者：
H. Naderi-Meshkin;M. Eleftheriadou;Garret Carney;V. A. Cornelius;Clare-Ann Nelson;Sophia Kelaini;
中科院分区：
文献类型：
--
作者：
H. Naderi-Meshkin;M. Eleftheriadou;Garret Carney;V. A. Cornelius;Clare-Ann Nelson;Sophia Kelaini;
内皮细胞（EC）和壁细胞两者的存在对于血管在健康和包括糖尿病在内的疾病的病理变化中的适当功能是至关重要的。虽然iPSC衍生的血管类器官（VO）提供了一个有吸引力的体外疾病模型和药物筛选平台，但这些类器官是否重现了人类疾病仍然存在争议。在这里，我们表明人类糖尿病（DB）-VO代表血管功能受损，包括增强的ROS活性，线粒体含量和活性较高，促炎细胞因子增加，体内再生潜力较低。使用单细胞RNA测序，我们鉴定了血管类器官内所有专门类型的血管细胞（动脉，毛细血管，静脉，淋巴和尖端细胞，以及周细胞和vSMC），同时展示了EC和壁细胞的二分法。此外，我们揭示了血管类器官内的基础异质性，并证明了糖尿病和非糖尿病VO之间的差异。值得注意的是，EC亚群显著富集DB-VO中的ROS和氧化磷酸化标志物，可能代表糖尿病中异常血管生成的早期迹象。这项研究有助于确定糖尿病疾病进展的关键生物标志物，并找到适合药物干预的信号分子。
The presence of both endothelial cells (ECs) and mural cells are central to the proper function of blood vessels in health and pathological changes in diseases including diabetes. Although iPSCs-derived vascular organoids (VOs) provide an appealing in vitro disease model and platform for drug screening, whether these organoids recapitulate human disease remains debatable. Here, we show human diabetic (DB)-VOs represent impaired vascular function including enhanced ROS activity, with higher mitochondrial content and activity, increased pro-inflammatory cytokines, and less regenerative potential in vivo. Using single-cell RNA sequencing, we identify all specialized types of vascular cells (artery, capillary, vein, lymphatic and tip cells, as well as pericytes and vSMCs) within vascular organoids, while demonstrating the dichotomy landscape of ECs and mural cells. Furthermore, we reveal basal heterogeneity within vascular organoids and demonstrate differences between diabetic and non-diabetic VOs. Of note, a subpopulation of ECs significantly enrich for ROS and oxidative phosphorylation hallmarks in DB-VOs, may represent early signs of aberrant angiogenesis in diabetes. This study helps to identify key biomarkers for diabetic disease progression and find signalling molecules amenable to drug intervention.