Drug Discovery Platform Targeting M. tuberculosis with Human Embryonic Stem Cell-Derived Macrophages
Drug Discovery Platform Targeting M. tuberculosis with Human Embryonic Stem Cell-Derived Macrophages
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DOI：
10.1016/j.stemcr.2019.10.002
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发表时间：
2019-12-10
影响因子：
5.9
通讯作者：
Kim, Jung-Hyun
中科院分区：
文献类型：
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作者：
Han, Hyo-Won;Seo, Hyang-Hee;Kim, Jung-Hyun
抗结核药物筛选的一个主要限制是缺乏可靠和可扩展的非癌来源的同质人原代巨噬细胞模型。在这里，我们报告了一个修改后的协议，产生同质群体的巨噬细胞样细胞从人胚胎干细胞。诱导的巨噬细胞（称为iMAC）呈现出与经典巨噬细胞相似的转录组学特征和特征性免疫学特征，并且允许病毒和细菌感染，特别是结核分枝杆菌（Mtb）。更重要的是，iMAC的生产可以扩大规模。为了评估iMAC在高通量抗结核药物筛选中的效率，我们对细胞内Mtb进行了表型筛选，涉及3，716种化合物的文库，其中包括FDA批准的药物和其他生物活性化合物。我们的初步筛选确定了120个命中，这是在二次筛选中通过剂量-细胞内和-细胞外Mtb测定验证。我们的验证性研究确定了一种新的抗结核化合物，10-DEBC，也显示出对耐药菌株的活性。
A major limitation in anti-tuberculosis drug screening is the lack of reliable and scalable models for homogeneous human primary macrophage cells of non-cancer origin. Here we report a modified protocol for generating homogeneous populations of macrophage-like cells from human embryonic stem cells. The induced macrophages, referred to as iMACs, presented similar transcriptomic profiles and characteristic immunological features of classical macrophages and were permissive to viral and bacterial infection, in particular Mycobacterium tuberculosis (Mtb). More importantly, iMAC production was amenable to scale up. To evaluate iMAC efficiency in high-throughput anti-tuberculosis drug screening, we performed a phenotypic screening against intracellular Mtb, involving a library of 3,716 compounds that included FDA-approved drugs and other bioactive compounds. Our primary screen identified 120 hits, which were validated in a secondary screen by dose-intracellular and -extracellular Mtb assays. Our confirmatory studies identified a novel anti-Mtb compound, 10-DEBC, also showing activity against drug-resistant strains.