Induced pluripotent stem cells from CINCA syndrome patients as a model for dissecting somatic mosaicism and drug discovery
Induced pluripotent stem cells from CINCA syndrome patients as a model for dissecting somatic mosaicism and drug discovery
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DOI：
10.1182/blood-2012-03-417881
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发表时间：
2012-08-09
期刊：
影响因子：
20.3
通讯作者：
Saito, Megumu K.
中科院分区：
文献类型：
--
作者：
Tanaka, Takayuki;Takahashi, Kazutoshi;Saito, Megumu K.
慢性婴儿神经性皮肤和关节（CINCA）综合征是一种主要由NLRP 3突变引起的IL-1驱动的自身炎症性疾病。携带NLRP 3突变的CINCA综合征患者的发病机制尚未被精确描述，因为难以根据突变的存在或不存在来分离单个细胞。在这里，我们报告了NLRP 3突变和非突变诱导的多能干细胞（iPSC）线从2 CINCA综合征患者与体细胞嵌合体的产生，并描述其分化成巨噬细胞（iPS-MP）。我们发现，突变细胞主要负责这些马赛克患者的发病机制，因为只有突变的iPS-MP显示异常IL-1 β分泌的疾病相关表型。我们还证实，现有的抗炎化合物抑制异常的IL-1 β分泌，表明突变的iPS-MP适用于CINCA综合征和其他NLRP 3相关炎症疾病的药物筛选。我们的研究结果表明，患者来源的iPSC可用于解剖体细胞嵌合现象，并且NLRP 3突变型iPSC可以为多种NLRP 3相关疾病的药物发现提供有价值的平台。（血。2012; 120（6）：1299-1308）
Chronic infantile neurologic cutaneous and articular (CINCA) syndrome is an IL-1-driven autoinflammatory disorder caused mainly by NLRP3 mutations. The pathogenesis of CINCA syndrome patients who carry NLRP3 mutations as somatic mosaicism has not been precisely described because of the difficulty in separating individual cells based on the presence or absence of the mutation. Here we report the generation of NLRP3-mutant and nonmutant-induced pluripotent stem cell (iPSC) lines from 2 CINCA syndrome patients with somatic mosaicism, and describe their differentiation into macrophages (iPS-MPs). We found that mutant cells are predominantly responsible for the pathogenesis in these mosaic patients because only mutant iPS-MPs showed the disease relevant phenotype of abnormal IL-1 beta secretion. We also confirmed that the existing anti-inflammatory compounds inhibited the abnormal IL-1 beta secretion, indicating that mutant iPS-MPs are applicable for drug screening for CINCA syndrome and other NLRP3-related inflammatory conditions. Our results illustrate that patient-derived iPSCs are useful for dissecting somatic mosaicism and that NLRP3-mutant iPSCs can provide a valuable platform for drug discovery for multiple NLRP3-related disorders. (Blood. 2012; 120(6):1299-1308)