Impairment of circulating endothelial progenitors in Down syndrome
Impairment of circulating endothelial progenitors in Down syndrome
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DOI：
10.1186/1755-8794-3-40
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发表时间：
2010-09-13
影响因子：
2.7
通讯作者：
Napoli, Claudio
中科院分区：
文献类型：
--
作者：
Costa, Valerio;Sommese, Linda;Napoli, Claudio
背景：病理性血管生成是许多疾病进展中的一个关键问题。唐氏综合症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因子的表达增加。我们研究的目的是阐明循环内皮祖细胞在这种综合征背景下的一些特征。方法：分离唐氏综合征患者循环内皮祖细胞，体外培养，共聚焦显微镜和透射电镜分析。ELISA检测唐氏综合征和整倍体患者血浆中SDF-1 α水平。此外，采用qRT-PCR方法定量CXCL12基因及其受体在祖细胞中的表达水平。通过BODIPY测定唐氏祖细胞对过氧化氢诱导的氧化应激的易感性和对人类病原体感染的主要易感性来评估唐氏祖细胞的功能损伤。通过微阵列分析评估唐氏祖细胞中关键基因的差异表达。结果：与整倍体相比，我们发现年轻唐氏个体的祖细胞数量明显减少，细胞大小增加，并出现一些主要的有害形态变化。此外，唐氏综合征患者血浆中SDF-1 α水平降低，其祖细胞中SDF-1 α编码基因及其膜受体表达降低。我们进一步证明，它们的祖细胞更容易受到过氧化氢诱导的氧化应激和感染亨selae巴尔通体。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，并且与感染的整倍体细胞相比，感染21三体的祖细胞具有更明显的免疫反应基因扰动。结论：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，也表明与整倍体细胞相比，唐氏综合征患者对氧化应激和病原体感染的易感性更高，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。
Background: 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.Methods: 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-1 alpha 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.Results: 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-1 alpha plasma levels and their progenitors had a reduced expression of SDF-1 alpha 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.Conclusions: 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.