Developmental Biology Program, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital, Chicago, IL, USA.
Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Sci Rep. 2020 Aug 6;10(1):13252. doi: 10.1038/s41598-020-69418-9.
Down syndrome (DS) is a congenital disorder caused by trisomy 21 (T21). It is associated with cognitive impairment, muscle hypotonia, heart defects, and other clinical anomalies. At the same time, individuals with Down syndrome have lower prevalence of solid tumor formation. To gain new insights into aberrant DS development during early stages of mesoderm formation and its possible connection to lower solid tumor prevalence, we developed the first model of two types of DS iPSC-derived stromal cells. Utilizing bioinformatic and functional analyses, we identified over 100 genes with coordinated expression among mesodermal and endothelial cell types. The most significantly down-regulated processes in DS mesodermal progenitors were associated with decreased stromal progenitor performance related to connective tissue organization as well as muscle development and functionality. The differentially expressed genes included cytoskeleton-related genes (actin and myosin), ECM genes (Collagens, Galectin-1, Fibronectin, Heparan Sulfate, LOX, FAK1), cell cycle genes (USP16, S1P complexes), and DNA damage repair genes. For DS endothelial cells, our analysis revealed most down-regulated genes associated with cellular response to external stimuli, cell migration, and immune response (inflammation-based). Together with functional assays, these results suggest an impairment in mesodermal development capacity during early stages, which likely translates into connective tissue impairment in DS patients. We further determined that, despite differences in functional processes and characteristics, a significant number of differentially regulated genes involved in tumorigenesis were expressed in a highly coordinated manner across endothelial and mesodermal cells. These findings strongly suggest that microRNAs (miR-24-4, miR-21), cytoskeleton remodeling, response to stimuli, and inflammation can impact resistance to tumorigenesis in DS patients. Furthermore, we also show that endothelial cell functionality is impaired, and when combined with angiogenic inhibition, it can provide another mechanism for decreased solid tumor development. We propose that the same processes, which specify the basis of connective tissue impairment observed in DS patients, potentially impart a resistance to cancer by hindering tumor progression and metastasis. We further establish that cancer-related genes on Chromosome 21 are up-regulated, while genome-wide cancer-related genes are down-regulated. These results suggest that trisomy 21 induces a modified regulation and compensation of many biochemical pathways across the genome. Such downstream interactions may contribute toward promoting tumor resistant mechanisms.
唐氏综合征（DS）是一种由 21 三体（T21）引起的先天性疾病。它与认知障碍、肌肉张力减退、心脏缺陷和其他临床异常有关。同时，唐氏综合征患者的实体瘤形成率较低。为了深入了解中胚层形成早期唐氏综合征发育的异常及其与较低实体瘤发生率的可能联系，我们开发了首例两种类型唐氏综合征诱导多能干细胞衍生基质细胞模型。通过生物信息学和功能分析，我们鉴定了 100 多个在中胚层和内皮细胞类型中协调表达的基因。唐氏综合征中胚层祖细胞中表达下调最显著的过程与与结缔组织组织、肌肉发育和功能相关的基质祖细胞性能降低有关。差异表达的基因包括细胞骨架相关基因（肌动蛋白和肌球蛋白）、细胞外基质基因（胶原、半乳糖凝集素-1、纤连蛋白、硫酸乙酰肝素、赖氨酰氧化酶、FAK1）、细胞周期基因（USP16、S1P 复合物）和 DNA 损伤修复基因。对于唐氏综合征内皮细胞，我们的分析表明，大多数下调的基因与细胞对外界刺激的反应、细胞迁移和免疫反应（炎症基础）有关。与功能测定相结合，这些结果表明在早期阶段中胚层发育能力受损，这可能导致唐氏综合征患者结缔组织受损。我们进一步确定，尽管在功能过程和特征上存在差异，但许多参与肿瘤发生的差异调节基因在血管内皮细胞和中胚层细胞中以高度协调的方式表达。这些发现强烈表明，微 RNA（miR-24-4、miR-21）、细胞骨架重塑、对刺激的反应和炎症可能会影响唐氏综合征患者对肿瘤发生的抵抗力。此外，我们还表明内皮细胞功能受损，当与血管生成抑制联合使用时，它可以为降低实体瘤的发展提供另一种机制。我们提出，在唐氏综合征患者中观察到的结缔组织损伤的基础过程，可能通过阻碍肿瘤的进展和转移，为癌症提供抵抗力。我们进一步确定，21 号染色体上的癌症相关基因上调，而全基因组癌症相关基因下调。这些结果表明，21 三体诱导了整个基因组中许多生化途径的调节和补偿的改变。这种下游相互作用可能有助于促进肿瘤抵抗机制。
