iPS cell-derived model to study the interaction between tissue macrophage and HIV-1
iPS cell-derived model to study the interaction between tissue macrophage and HIV-1
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DOI：
10.1093/jleuko/qiad024
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发表时间：
2023-04-06
影响因子：
5.5
通讯作者：
Suzu, Shinya
中科院分区：
文献类型：
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作者：
Eltalkhawy, Youssef M.;Takahashi, Naofumi;Suzu, Shinya
本研究确定了一个自我更新的巨噬细胞模型，适合模仿HIV-1和组织巨噬细胞之间的相互作用，尽管有效的抗逆转录病毒治疗，HIV-1持续存在于细胞，包括巨噬细胞，这是一个障碍，以治愈。然而，巨噬细胞在HIV-1感染中的确切作用仍不清楚，因为它们存在于不易接近的组织中。单核细胞来源的巨噬细胞被广泛用作培养外周血单核细胞并分化成巨噬细胞的模型。然而，需要另一种模型，因为最近的研究表明，成人组织中的大多数巨噬细胞来源于卵黄囊和胎肝前体细胞，而不是单核细胞，并且胚胎巨噬细胞具有单核细胞衍生的巨噬细胞缺乏的自我更新（增殖）能力。在这里，我们表明，人诱导多能干细胞衍生的永生化巨噬细胞样细胞是一个有用的自我更新的巨噬细胞模型。它们以嘌呤依赖性方式增殖，保留巨噬细胞功能，支持HIV-1复制，并表现出感染的单核细胞衍生的巨噬细胞样表型，如增强的隧道纳米管形成和细胞运动性，以及对病毒致细胞病变效应的抗性。然而，在单核细胞衍生的巨噬细胞和诱导多能干细胞衍生的永生化巨噬细胞样细胞之间也观察到若干差异，其中大部分可以通过诱导多能干细胞衍生的永生化巨噬细胞样细胞的增殖来解释。例如，在接受抗逆转录病毒治疗的个体中随着时间的推移而增加的具有大的内部缺失的前病毒在诱导多能干细胞衍生的永生化巨噬细胞样细胞中更快地富集。有趣的是，HIV-1抑制剂对病毒转录的抑制在诱导多能干细胞衍生的永生化巨噬细胞样细胞中更为明显。总的来说，我们目前的研究提出，诱导多能干细胞衍生的永生化巨噬细胞样细胞的模型适合于模仿HIV-1和自我更新组织巨噬细胞之间的相互作用，这是大多数组织中新认识到的主要群体，不能完全由单核细胞衍生的巨噬细胞单独建模。
The present study identifies a self-renewing macrophage model suitable for mimicking the interplay between HIV-1 and tissue macrophages.Despite effective antiretroviral therapy, HIV-1 persists in cells, including macrophages, which is an obstacle to cure. However, the precise role of macrophages in HIV-1 infection remains unclear because they reside in tissues that are not easily accessible. Monocyte-derived macrophages are widely used as a model in which peripheral blood monocytes are cultured and differentiated into macrophages. However, another model is needed because recent studies revealed that most macrophages in adult tissues originate from the yolk sac and fetal liver precursors rather than monocytes, and the embryonic macrophages possess a self-renewal (proliferating) capacity that monocyte-derived macrophages lack. Here, we show that human induced pluripotent stem cell-derived immortalized macrophage-like cells are a useful self-renewing macrophage model. They proliferate in a cytokine-dependent manner, retain macrophage functions, support HIV-1 replication, and exhibit infected monocyte-derived macrophage-like phenotypes, such as enhanced tunneling nanotube formation and cell motility, as well as resistance to a viral cytopathic effect. However, several differences are also observed between monocyte-derived macrophages and induced pluripotent stem cell-derived immortalized macrophage-like cells, most of which can be explained by the proliferation of induced pluripotent stem cell-derived immortalized macrophage-like cells. For instance, proviruses with large internal deletions, which increased over time in individuals receiving antiretroviral therapy, are enriched more rapidly in induced pluripotent stem cell-derived immortalized macrophage-like cells. Interestingly, inhibition of viral transcription by HIV-1-suppressing agents is more obvious in induced pluripotent stem cell-derived immortalized macrophage-like cells. Collectively, our present study proposes that the model of induced pluripotent stem cell-derived immortalized macrophage-like cells is suitable for mimicking the interplay between HIV-1 and self-renewing tissue macrophages, the newly recognized major population in most tissues that cannot be fully modeled by monocyte-derived macrophages alone.