Institute of Genetics and Biophysics A, Buzzati-Traverso, IGB-CNR, Naples, Italy.
BMC Med Genomics. 2010 Sep 13;3:40. doi: 10.1186/1755-8794-3-40.
Pathological angiogenesis represents a critical issue in the progression of many diseases. Down syndrome is postulated to be a systemic anti-angiogenesis disease model, possibly due to increased expression of anti-angiogenic regulators on chromosome 21. The aim of our study was to elucidate some features of circulating endothelial progenitor cells in the context of this syndrome.
Circulating endothelial progenitors of Down syndrome affected individuals were isolated, in vitro cultured and analyzed by confocal and transmission electron microscopy. ELISA was performed to measure SDF-1α plasma levels in Down syndrome and euploid individuals. Moreover, qRT-PCR was used to quantify expression levels of CXCL12 gene and of its receptor in progenitor cells. The functional impairment of Down progenitors was evaluated through their susceptibility to hydroperoxide-induced oxidative stress with BODIPY assay and the major vulnerability to the infection with human pathogens. The differential expression of crucial genes in Down progenitor cells was evaluated by microarray analysis.
We detected a marked decrease of progenitors' number in young Down individuals compared to euploid, cell size increase and some major detrimental morphological changes. Moreover, Down syndrome patients also exhibited decreased SDF-1α plasma levels and their progenitors had a reduced expression of SDF-1α encoding gene and of its membrane receptor. We further demonstrated that their progenitor cells are more susceptible to hydroperoxide-induced oxidative stress and infection with Bartonella henselae. Further, we observed that most of the differentially expressed genes belong to angiogenesis, immune response and inflammation pathways, and that infected progenitors with trisomy 21 have a more pronounced perturbation of immune response genes than infected euploid cells.
Our data provide evidences for a reduced number and altered morphology of endothelial progenitor cells in Down syndrome, also showing the higher susceptibility to oxidative stress and to pathogen infection compared to euploid cells, thereby confirming the angiogenesis and immune response deficit observed in Down syndrome individuals.
病理性血管生成是许多疾病进展过程中的一个关键问题。唐氏综合征被认为是一种全身性抗血管生成疾病模型，可能是由于 21 号染色体上抗血管生成调节剂表达增加所致。我们的研究目的是阐明唐氏综合征患者循环内皮祖细胞的一些特征。
分离唐氏综合征患者的循环内皮祖细胞，体外培养并通过共聚焦和透射电子显微镜进行分析。采用 ELISA 法测定唐氏综合征和正常二倍体个体的 SDF-1α 血浆水平。此外，采用 qRT-PCR 法检测祖细胞中 CXCL12 基因及其受体的表达水平。通过 BODIPY 测定法评估过氧化物诱导的氧化应激对唐氏祖细胞的功能损伤，以及人类病原体感染的主要易感性。通过微阵列分析评估唐氏祖细胞中关键基因的差异表达。
我们发现，与正常二倍体相比，年轻唐氏个体的祖细胞数量明显减少，细胞体积增大，形态发生了一些主要的不利变化。此外，唐氏综合征患者的 SDF-1α 血浆水平也降低，其祖细胞的 SDF-1α 编码基因及其膜受体表达减少。我们进一步证明，唐氏综合征患者的祖细胞对过氧化氢诱导的氧化应激和感染亨氏巴尔通体更为敏感。此外，我们观察到大多数差异表达的基因属于血管生成、免疫反应和炎症途径，并且感染三体 21 的祖细胞比感染正常二倍体的细胞具有更明显的免疫反应基因失调。
我们的数据提供了唐氏综合征患者内皮祖细胞数量减少和形态改变的证据，还表明与正常二倍体细胞相比，唐氏综合征患者的祖细胞对氧化应激和病原体感染的敏感性更高，从而证实了唐氏综合征患者观察到的血管生成和免疫反应缺陷。
