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尼杰梅根断裂综合征成纤维细胞和 iPSC：揭示疾病相关信号通路的细胞模型，以及建立抗氧化剂筛选平台。

Nijmegen Breakage Syndrome fibroblasts and iPSCs: cellular models for uncovering disease-associated signaling pathways and establishing a screening platform for anti-oxidants.

机构信息

Max-Delbrück-Centrum für Molekulare Medizin (MDC), 13092, Berlin, Germany.

Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich Heine University, 40225, Düsseldorf, Germany.

出版信息

Sci Rep. 2017 Aug 8;7(1):7516. doi: 10.1038/s41598-017-07905-2.

DOI:10.1038/s41598-017-07905-2
PMID:28790359
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5548734/
Abstract

Nijmegen Breakage Syndrome (NBS) is associated with cancer predisposition, premature aging, immune deficiency, microcephaly and is caused by mutations in the gene coding for NIBRIN (NBN) which is involved in DNA damage repair. Dermal-derived fibroblasts from NBS patients were reprogrammed into induced pluripotent stem cells (iPSCs) in order to bypass premature senescence. The influence of antioxidants on intracellular levels of ROS and DNA damage were screened and it was found that EDHB-an activator of the hypoxia pathway, decreased DNA damage in the presence of high oxidative stress. Furthermore, NBS fibroblasts but not NBS-iPSCs were found to be more susceptible to the induction of DNA damage than their healthy counterparts. Global transcriptome analysis comparing NBS to healthy fibroblasts and NBS-iPSCs to embryonic stem cells revealed regulation of P53 in NBS fibroblasts and NBS-iPSCs. Cell cycle related genes were down-regulated in NBS fibroblasts. Furthermore, oxidative phosphorylation was down-regulated and glycolysis up-regulated specifically in NBS-iPSCs compared to embryonic stem cells. Our study demonstrates the utility of NBS-iPSCs as a screening platform for anti-oxidants capable of suppressing DNA damage and a cellular model for studying NBN de-regulation in cancer and microcephaly.

摘要

尼曼匹克破碎综合征（NBS）与癌症易感性、早衰、免疫缺陷、小头畸形有关，是由编码 NIBRIN（NBN）的基因突变引起的，该基因参与 DNA 损伤修复。为了绕过早衰，从 NBS 患者的皮肤衍生成纤维细胞被重编程为诱导多能干细胞（iPSCs）。筛选了抗氧化剂对细胞内 ROS 和 DNA 损伤水平的影响，发现 EDHB（缺氧途径的激活剂）在高氧化应激条件下降低了 DNA 损伤。此外，与健康对照组相比，NBS 成纤维细胞而非 NBS-iPSCs 更容易受到 DNA 损伤的诱导。将 NBS 与健康成纤维细胞进行比较，将 NBS-iPSCs 与胚胎干细胞进行比较的全转录组分析显示，P53 在 NBS 成纤维细胞和 NBS-iPSCs 中受到调控。NBS 成纤维细胞中细胞周期相关基因下调。此外，与胚胎干细胞相比，NBS-iPSCs 中氧化磷酸化下调，糖酵解上调。我们的研究表明，NBS-iPSCs 可作为一种筛选平台，用于筛选能够抑制 DNA 损伤的抗氧化剂，并可作为研究 NBN 失调与癌症和小头畸形的细胞模型。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f7ed/5548734/7de71c763008/41598_2017_7905_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f7ed/5548734/1c2381bd2d17/41598_2017_7905_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f7ed/5548734/a90043eff261/41598_2017_7905_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f7ed/5548734/ce0f988d3920/41598_2017_7905_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f7ed/5548734/7de71c763008/41598_2017_7905_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f7ed/5548734/1c2381bd2d17/41598_2017_7905_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f7ed/5548734/a90043eff261/41598_2017_7905_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f7ed/5548734/ce0f988d3920/41598_2017_7905_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f7ed/5548734/7de71c763008/41598_2017_7905_Fig4_HTML.jpg

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