The circadian regulator PER1 promotes cell reprogramming by inhibiting inflammatory signaling from macrophages.
The circadian regulator PER1 promotes cell reprogramming by inhibiting inflammatory signaling from macrophages.
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DOI：
10.1371/journal.pbio.3002419
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发表时间：
2023-12
期刊：
影响因子：
9.8
通讯作者：
Kikyo, Nobuaki
中科院分区：
文献类型：
--
作者：
Katoku-Kikyo, Nobuko;Lim, Seunghyun;Yuan, Ce;Koroth, Jinsha;Nakagawa, Yasushi;Bradley, Elizabeth W.;Kikyo, Nobuaki
基因表达的昼夜节律是普遍存在的，在细胞分化中起着关键作用。然而，它在分化细胞重新编程中的作用在很大程度上仍不清楚。在这里，我们发现主要的昼夜节律调节因子之一PER1促进病毒介导的小鼠胚胎成纤维细胞(MEF)向诱导神经元(INS)和诱导多能干细胞(IPSCs)的重编程。出乎意料的是，PER1通过抑制MEF培养中受污染的巨噬细胞的炎症激活而实现了这一点，而不是通过直接调节MEF的可重编程性。更具体地说，我们发现转导的病毒激活了巨噬细胞中的炎症基因，例如编码肿瘤坏死因子α的肿瘤坏死因子，它是中枢性炎症调节因子之一，也是巨噬细胞的自分泌激活剂。肿瘤坏死因子α抑制重编程，而肿瘤坏死因子α抑制剂促进重编程，将炎症反应与重编程联系起来。此外，非巨噬细胞作为饲养者可诱导巨噬细胞增殖和成熟，这也支持在没有病毒转导的情况下上调巨噬细胞中肿瘤坏死因子α的表达。此外，这两种炎症反应被巨噬细胞中的昼夜节律调节因子PER1抑制，使可重编性依赖于病毒转导的时间。IPSC重编程也得到了类似的结果，表明巨噬细胞介导的细胞重编程抑制广泛发生。这项研究揭示了细胞重编程、旁观者炎性巨噬细胞和昼夜节律之间的机械联系，这与体内重编程和结合免疫细胞的有机物形成特别相关。基因表达的昼夜节律调节在细胞分化中起着关键作用，但分化细胞的重新编程又如何呢？这项研究表明，在成纤维细胞培养中，污染的巨噬细胞在重新编程为神经元和多能干细胞的过程中发挥了意想不到的抑制作用，这是由昼夜节律基因PER1控制的。
Circadian regulation of gene expression is prevalent and plays critical roles in cell differentiation. However, its roles in the reprogramming of differentiated cells remain largely unknown. Here, we found that one of the master circadian regulators PER1 promoted virus-mediated reprogramming of mouse embryonic fibroblasts (MEFs) to induced neurons (iNs) and induced pluripotent stem cells (iPSCs). Unexpectedly, PER1 achieved this by repressing inflammatory activation of contaminating macrophages in the MEF culture, rather than by directly modulating the reprogrammability of MEFs. More specifically, we found that transduced viruses activated inflammatory genes in macrophages, such as Tnf encoding TNFα, one of the central inflammatory regulators and an autocrine activator of macrophages. TNFα inhibited iN reprogramming, whereas a TNFα inhibitor promoted iN reprogramming, connecting the inflammatory responses to iN reprogramming. In addition, macrophages were induced to proliferate and mature by non-macrophage cells serving as feeders, which also supported up-regulation of TNFα in macrophages without virus transduction. Furthermore, the 2 inflammatory responses were repressed by the circadian regulator PER1 in macrophages, making reprogrammability dependent on time-of-day of virus transduction. Similar results were obtained with iPSC reprogramming, suggesting a wide occurrence of macrophage-mediated inhibition of cell reprogramming. This study uncovers mechanistic links between cell reprogramming, bystander inflammatory macrophages, and circadian rhythms, which are particularly relevant to in vivo reprogramming and organoid formation incorporating immune cells. Circadian regulation of gene expression plays critical roles in cell differentiation, but what about reprogramming of differentiated cells? This study shows that contaminating macrophages in fibroblast culture play unsuspected inhibitory roles during reprogramming to neurons and pluripotent stem cells, controlled by the circadian rhythm gene Per1.
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影响因子：
9
作者：
Poole J;Kitchen GB
通讯作者：
Kitchen GB
DOI：
10.1073/pnas.1106750109
发表时间：
2012-01-10
影响因子：
11.1
作者：
Gibbs, Julie E.;Blaikley, John;Loudon, Andrew S. I.
通讯作者：
Loudon, Andrew S. I.
影响因子：
46.9
作者：
Bouffi, Carine;Wikenheiser-Brokamp, Kathryn A.;Chaturvedi, Praneet;Sundaram, Nambirajan;Goddard, Gillian R.;Wunderlich, Mark;Brown, Nicole E.;Staab, Janet F.;Latanich, Rachel;Zachos, Nicholas C.;Holloway, Emily M.;Mahe, Maxime M.;Poling, Holly M.;Vales, Simon;Fisher, Garrett W.;Spence, Jason R.;Mulloy, James C.;Zorn, Aaron M.;Wells, James M.;Helmrath, Michael A.
通讯作者：
Helmrath, Michael A.
影响因子：
7
作者：
Collins EJ;Cervantes-Silva MP;Timmons GA;O'Siorain JR;Curtis AM;Hurley JM
通讯作者：
Hurley JM
自适应免疫，慢性炎症和时钟。
影响因子：
9
作者：
Gray KJ;Gibbs JE
通讯作者：
Gibbs JE