Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA; Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Cell Rep. 2022 Aug 9;40(6):111174. doi: 10.1016/j.celrep.2022.111174.
Despite the prevalence of Down syndrome (DS), little is known regarding the specific cell pathologies that underlie this multi-system disorder. To understand which cell types and pathways are more directly affected by trisomy 21 (T21), we used an inducible-XIST system to silence one chromosome 21 in vitro. T21 caused the dysregulation of Notch signaling in iPSCs, potentially affecting cell-type programming. Further analyses identified dysregulation of pathways important for two cell types: neurogenesis and angiogenesis. Angiogenesis is essential to many bodily systems, yet is understudied in DS; therefore, we focused next on whether T21 affects endothelial cells. An in vitro assay for microvasculature formation revealed a cellular pathology involving delayed tube formation in response to angiogenic signals. Parallel transcriptomic analysis of endothelia further showed deficits in angiogenesis regulators. Results indicate a direct cell-autonomous impact of T21 on endothelial function, highlighting the importance of angiogenesis, with wide-reaching implications for development and disease progression.
尽管唐氏综合征（Down syndrome，DS）较为常见，但对于导致这种多系统疾病的具体细胞病理学知之甚少。为了了解哪些细胞类型和途径更直接受到 21 三体（trisomy 21，T21）的影响，我们使用诱导型 XIST 系统在体外沉默一条 21 号染色体。T21 导致 iPSCs 中的 Notch 信号失调，可能影响细胞类型编程。进一步的分析确定了对两种细胞类型（神经发生和血管生成）重要的途径失调。血管生成对于许多身体系统都是必不可少的，但在 DS 中研究较少；因此，我们接下来专注于 T21 是否影响内皮细胞。体外微血管形成测定显示，在对血管生成信号的反应中，存在涉及管腔形成延迟的细胞病理学。对内皮细胞的平行转录组分析进一步显示出血管生成调节剂的缺陷。结果表明 T21 对内皮功能具有直接的细胞自主性影响，突出了血管生成的重要性，对发育和疾病进展具有广泛影响。
