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PCDH15 Dual-AAV Gene Therapy for Deafness and Blindness in Usher Syndrome Type 1F Models. PCDH15 双 AAV 基因疗法治疗乌谢尔综合征 1F 型模型的失聪和失明。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-15 DOI: 10.1172/JCI177700
Maryna V Ivanchenko, Daniel M Hathaway, Eric M Mulhall, Kevin Ta Booth, Mantian Wang, Cole W Peters, Alex J Klein, Xinlan Chen, Yaqiao Li, Bence György, David P Corey

Usher syndrome type 1F (USH1F), resulting from mutations in the protocadherin-15 (PCDH15) gene, is characterized by congenital lack of hearing and balance, and progressive blindness in the form of retinitis pigmentosa. In this study, we explore an approach for USH1F gene therapy, exceeding the single AAV packaging limit by employing a dual adeno-associated virus (AAV) strategy to deliver the full-length PCDH15 coding sequence. We demonstrate the efficacy of this strategy in mouse USH1F models, effectively restoring hearing and balance in these mice. Importantly, our approach also proves successful in expressing PCDH15 protein in clinically relevant retinal models, including human retinal organoids and non-human primate retina, showing efficient targeting of photoreceptors and proper protein expression in the calyceal processes. This research represents a major step toward advancing gene therapy for USH1F and the multiple challenges of hearing, balance, and vision impairment.

1F型乌谢尔综合征(USH1F)是由原粘连蛋白-15(PCDH15)基因突变引起的,其特征是先天性听力和平衡感缺失,并以视网膜色素变性的形式进行性失明。在这项研究中,我们探索了一种 USH1F 基因治疗方法,通过采用双重腺相关病毒 (AAV) 策略来传递全长 PCDH15 编码序列,从而突破了单一 AAV 包装的限制。我们在小鼠 USH1F 模型中证明了这一策略的有效性,有效恢复了这些小鼠的听力和平衡能力。重要的是,我们的方法还成功地在临床相关视网膜模型(包括人类视网膜器官组织和非人灵长类视网膜)中表达了 PCDH15 蛋白,显示了光感受器的高效靶向性和萼状过程中蛋白质的正确表达。这项研究标志着我们在推进针对 USH1F 以及听力、平衡和视力损伤等多重挑战的基因疗法方面迈出了重要一步。
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引用次数: 0
Reactive microglia partially envelop viable neurons in prion diseases. 在朊病毒疾病中,反应性小胶质细胞部分包裹着有活力的神经元。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-03 DOI: 10.1172/JCI181169
Natallia Makarava, Tarek Safadi, Olga Bocharova, Olga Mychko, Narayan P Pandit, Kara Molesworth, Simone Baiardi, Li Zhang, Piero Parchi, Ilia V Baskakov

Microglia are recognized as the main cells in the central nervous system responsible for phagocytosis. The current study demonstrated that in prion disease, microglia effectively phagocytose prions or PrPSc during early preclinical stages. However, a critical shift occured in microglial activity during the late preclinical stage, transitioning from PrPSc uptake to establishing extensive neuron-microglia body-to-body cell contacts. This change was followed by a rapid accumulation of PrPSc in the brain. Microglia that enveloped neurons exhibited hypertrophic, cathepsin D-positive lysosomal compartments. However, most neurons undergoing envelopment were only partially encircled by microglia. Despite up to 40% of cortical neurons being partially enveloped at clinical stages, only a small percentage of envelopment proceeded to full engulfment. Partially enveloped neurons lacked apoptotic markers but showed signs of functional decline. Neuronal envelopment was independent of the CD11b pathway, previously associated with phagocytosis of newborn neurons during neurodevelopment. This phenomenon of partial envelopment was consistently observed across multiple prion-affected brain regions, various mouse-adapted strains, and different subtypes of sporadic Creutzfeldt-Jakob disease (sCJD) in humans. The current work describes a new phenomenon of partial envelopment of neurons by reactive microglia in the context of an actual neurodegenerative disease, not a disease model.

小胶质细胞被认为是中枢神经系统中负责吞噬的主要细胞。目前的研究表明,在朊病毒病早期临床阶段,小胶质细胞能有效吞噬朊病毒或PrPSc。然而,在临床前晚期,小胶质细胞的活动发生了关键性转变,从摄取PrPSc过渡到建立广泛的神经元-小胶质细胞体-体细胞接触。这一变化之后,PrPSc 在大脑中迅速积累。包绕神经元的小胶质细胞表现出肥大的、溶酶体D阳性的溶酶体区。然而,大多数被包绕的神经元仅被小胶质细胞部分包绕。尽管高达 40% 的皮质神经元在临床阶段被部分包绕,但只有一小部分包绕神经元被完全吞噬。部分被包绕的神经元缺乏凋亡标记,但有功能衰退的迹象。神经元包膜与 CD11b 通路无关,而 CD11b 通路以前与神经发育过程中新生神经元的吞噬作用有关。这种部分包膜现象在多个受朊病毒影响的脑区、各种小鼠适配品系和人类散发性克雅氏病(sCJD)的不同亚型中都得到了一致观察。目前的研究工作描述了反应性小胶质细胞在实际神经退行性疾病(而非疾病模型)背景下部分包绕神经元的新现象。
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引用次数: 0
Transcription factor KROX20 marks epithelial stem cells for hair follicle formation. 转录因子 KROX20 标志着上皮干细胞的毛囊形成。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-03 DOI: 10.1172/JCI180160
Elnaz Ghotbi, Edem Tchegnon, Zhiguo Chen, Stephen Li, Tracey Shipman, Yong Wang, Jenny Raman, Yumeng Zhang, Renee M McKay, Chung-Ping Liao, Lu Q Le

Epidermal stem cells control homeostasis and regeneration of skin and hair. In the hair follicle (HF) bulge of mammals, populations of slow-cycling stem cells regenerate the HF during cyclical rounds of anagen (growth), telogen (quiescence), and catagen (regression). Multipotent epidermal cells are also present in the HF above the bulge area, contributing to the formation and maintenance of sebaceous gland and upper and middle portions of the HF. Here, we report that the transcription factor Krox20 is enriched in an epidermal stem cell population located in the upper/ middle HF. Expression analyses and lineage tracing using inducible Krox20-CreERT showed that Krox20-lineage cells migrate out of this HF region and contribute to the formation of bulge in the HF, serving as ancestors of bulge stem cells. In vivo depletion of these cells arrests HF morphogenesis. This study identifies a novel marker for an epidermal stem cell population that is indispensable for hair homeostasis.

表皮干细胞控制着皮肤和毛发的平衡与再生。在哺乳动物的毛囊隆起区,缓慢循环的干细胞群在周期性的生长期(生长)、休止期(静止)和衰退期(衰退)中再生毛囊隆起区。多能表皮细胞也存在于隆起区上方的高频,有助于皮脂腺和高频中上部的形成和维持。在这里,我们报告了转录因子Krox20在位于HF中上部的表皮干细胞群中的富集情况。使用诱导性Krox20-CreERT进行的表达分析和系谱追踪显示,Krox20系细胞迁移出这一HF区域,促进了HF中隆起的形成,成为隆起干细胞的祖先。体内去除了这些细胞,高频形态发生就会停止。这项研究为毛发稳态不可或缺的表皮干细胞群确定了一种新的标记。
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引用次数: 0
Viral infection induces inflammatory signals that coordinate YAP regulation of dysplastic cells in lung alveoli. 病毒感染会诱发炎症信号,从而协调肺泡中发育不良细胞的 YAP 调节。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 DOI: 10.1172/JCI176828
Xiuyu Lin, Weicheng Chen, Guilin Yang, Jiazhu Zhang, Huilin Wang, Zeyu Liu, Ying Xi, Tao Ren, Bo Liu, Pengfei Sui

Severe viral pneumonia can induce rapid expansion of KRT5+ basal-like cells in small airways and alveoli; this forms a scar-like structure that persists in the injured alveoli and impedes normal alveolar epithelium regeneration. In this study, we investigated the mechanism by which viral infection induced this remodeling response. Through comparing different lung-injury models, we demonstrated that infection induced strong IFN-γ signal-stimulated dysplastic KRT5+ cell formation. Inactivation of interferon receptor 1 (Ifngr1) reduced dysplastic cell formation, ameliorated lung fibrosis, and improved lung-function recovery. Mechanistically, IFN-γ regulated dysplastic cell formation via the focal adhesion kinase (FAK)/Yes-associated protein 1 (YAP) pathway. Inhibiting FAK/Src diminished IFN-γ-induced YAP nuclear translocation and dysplastic cell formation. Inhibiting YAP during viral infection prevented dysplastic cell formation, whereas inhibiting YAP in persistent KRT5+ cells led to their conversion into distal club cells. Importantly, human dysplastic cells exhibited elevated FAK and YAP activity, and IFN-γ treatment promoted the transformation of human alveolar progenitor cells into dysplastic cells. These findings uncover the role of infection-induced inflammatory response in alveolar remodeling and may provide potential therapeutic avenues for the treatment of alveolar remodeling in patients with severe viral pneumonia.

重症病毒性肺炎可诱导小气道和肺泡中的 KRT5+基底样细胞迅速扩张;这会形成一种疤痕样结构,持续存在于受伤的肺泡中,阻碍肺泡上皮的正常再生。在这项研究中,我们探讨了病毒感染诱导这种重塑反应的机制。通过比较不同的肺损伤模型,我们发现感染诱导了强烈的 IFN-γ 信号刺激了发育不良的 KRT5+ 细胞形成。干扰素受体1(Ifngr1)的失活减少了发育不良细胞的形成,改善了肺纤维化,并提高了肺功能的恢复。从机理上讲,IFN-γ通过局灶粘附激酶(FAK)/Yes相关蛋白1(YAP)途径调节发育不良细胞的形成。抑制FAK/Src可减少IFN-γ诱导的YAP核转位和发育不良细胞的形成。在病毒感染期间抑制 YAP 可防止发育不良细胞的形成,而在持续存在的 KRT5+ 细胞中抑制 YAP 则会导致它们转化为远端俱乐部细胞。重要的是,人类发育不良细胞表现出FAK和YAP活性升高,IFN-γ处理促进了人类肺泡祖细胞向发育不良细胞的转化。这些发现揭示了感染诱导的炎症反应在肺泡重塑中的作用,并为治疗重症病毒性肺炎患者的肺泡重塑提供了潜在的治疗途径。
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引用次数: 0
The emergence of clonal hematopoiesis as a disease determinant. 克隆造血作为疾病决定因素的出现。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 DOI: 10.1172/JCI180063
Kenneth Walsh
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引用次数: 0
Clonal hematopoiesis and hematological malignancy. 克隆造血和血液恶性肿瘤。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 DOI: 10.1172/JCI180065
William G Dunn, Matthew A McLoughlin, George S Vassiliou

Clonal hematopoiesis (CH), the expansion of hematopoietic stem cells and their progeny driven by somatic mutations in leukemia-associated genes, is a common phenomenon that rises in prevalence with advancing age to affect most people older than 70 years. CH remains subclinical in most carriers, but, in a minority, it progresses to a myeloid neoplasm, such as acute myeloid leukemia, myelodysplastic syndrome, or myeloproliferative neoplasm. Over the last decade, advances in our understanding of CH, its molecular landscape, and the risks associated with different driver gene mutations have culminated in recent developments that allow for a more precise estimation of myeloid neoplasia risk in CH carriers. In turn, this is leading to the development of translational and clinical programs to intercept and prevent CH from developing into myeloid neoplasia. Here, we give an overview of the spectrum of CH driver mutations, what is known about their pathophysiology, and how this informs the risk of incident myeloid malignancy.

克隆性造血(CH)是指造血干细胞及其后代在白血病相关基因体细胞突变的驱动下发生扩增,是一种常见现象,随着年龄的增长,其发病率也会上升,影响大多数 70 岁以上的老人。在大多数携带者中,CH 仍处于亚临床状态,但在少数携带者中,CH 会发展为髓细胞肿瘤,如急性髓细胞白血病、骨髓增生异常综合征或骨髓增殖性肿瘤。在过去的十年中,我们对CH、其分子结构以及不同驱动基因突变相关风险的了解不断加深,最近的研究成果使我们能够更精确地估计CH携带者罹患髓系肿瘤的风险。反过来,这也促进了转化和临床项目的发展,以拦截和预防CH发展为髓样肿瘤。在此,我们将概述CH驱动基因突变的范围、对其病理生理学的了解,以及这如何影响髓系恶性肿瘤的发病风险。
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引用次数: 0
Neuropilin-2 expressing cells in breast cancer are S-nitrosylation hubs that mitigate radiation-induced oxidative stress. 乳腺癌中表达 Neuropilin-2 的细胞是 S-亚硝基化枢纽,可减轻辐射诱导的氧化应激。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 DOI: 10.1172/JCI181368
Ayush Kumar, Hira Goel, Christi Wisniewski, Tao Wang, Yansong Geng, Mengdie Wang, Shivam Goel, Kai Hu, Rui Li, Lihua J Zhu, Jennifer L Clark, Lindsay M Ferreira, Michael Brehm, Thomas J Fitzgerald, Arthur M Mercurio

The high rate of recurrence after radiation therapy in triple-negative breast cancer (TNBC) indicates that novel approaches and targets are needed to enhance radiosensitivity. Here, we report that neuropilin-2 (NRP2), a receptor for vascular endothelial growth factor (VEGF) that is enriched on sub-populations of TNBC cells with stem cell properties, is an effective therapeutic target for sensitizing TNBC to radiotherapy. Specifically, VEGF/NRP2 signaling induces nitric oxide synthase 2 (NOS2) transcription by a mechanism dependent on Gli1. NRP2-expressing tumor cells serve as a hub to produce nitric oxide (NO), an autocrine and paracrine signaling metabolite, which promotes cysteine-nitrosylation of Kelch-like ECH-asssociated protein 1 (KEAP1) and, consequently, nuclear factor erythroid 2-related factor 2 (NFE2L2)-mediated transcription of antioxidant response genes. Inhibiting VEGF binding to NRP2, using a humanized monoclonal antibody (mAb), results in NFE2L2 degradation via KEAP1 rendering cell lines and organoids vulnerable to irradiation. Importantly, treatment of patient-derived xenografts with the NRP2 mAb and radiation resulted in significant tumor necrosis and regression compared to radiation alone. Together, these findings reveal a targetable mechanism of radioresistance and they support the use of NRP2 mAb as an effective radiosensitizer in TNBC.

三阴性乳腺癌(TNBC)放疗后的高复发率表明,需要新的方法和靶点来提高放射敏感性。在这里,我们报告了神经鞘氨醇-2(NRP2)是血管内皮生长因子(VEGF)的受体,它富集在具有干细胞特性的TNBC细胞亚群中,是使TNBC对放疗敏感的有效治疗靶点。具体来说,VEGF/NRP2信号通过依赖Gli1的机制诱导一氧化氮合酶2(NOS2)转录。NRP2表达的肿瘤细胞是产生一氧化氮(NO)的枢纽,一氧化氮是一种自分泌和旁分泌信号代谢产物,它促进Kelch样ECH相关蛋白1(KEAP1)的半胱氨酸-亚硝基化,进而促进核因子红细胞2相关因子2(NFE2L2)介导的抗氧化反应基因的转录。使用人源化单克隆抗体(mAb)抑制血管内皮生长因子与 NRP2 的结合会导致 NFE2L2 通过 KEAP1 降解,从而使细胞系和器官组织易受辐照影响。重要的是,用 NRP2 mAb 和辐射处理患者衍生的异种移植物会导致肿瘤显著坏死和消退,而只用辐射则不会导致肿瘤坏死和消退。这些发现共同揭示了放射抗性的靶向机制,并支持使用 NRP2 mAb 作为 TNBC 的有效放射增敏剂。
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引用次数: 0
IL-7-dependent and -independent lineages of IL-7R-dependent human T cells. 依赖 IL-7R 的人类 T 细胞的 IL-7 依赖系和非依赖系。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 DOI: 10.1172/JCI180251
Carlos A Arango-Franco, Masato Ogishi, Susanne Unger, Ottavia M Delmonte, Julio César Orrego, Ahmad Yatim, Margarita M Velasquez-Lopera, Andrés F Zea-Vera, Jonathan Bohlen, Marwa Chbihi, Antoine Fayand, Juan Pablo Sánchez, Julian Rojas, Yoann Seeleuthner, Tom Le Voyer, Quentin Philippot, Kathryn J Payne, Adrian Gervais, Lucia V Erazo-Borrás, Luis A Correa-Londoño, Axel Cederholm, Alejandro Gallón-Duque, Pedro Goncalves, Jean-Marc Doisne, Liran Horev, Bénédicte Charmeteau-de Muylder, Jesús Á Álvarez, Diana M Arboleda, Lizet Pérez-Zapata, Estefanía Vásquez-Echeverri, Marcela Moncada-Vélez, Juan A López, Yolanda Caicedo, Boaz Palterer, Pablo J Patiño, Carlos J Montoya, Matthieu Chaldebas, Peng Zhang, Tina Nguyen, Cindy S Ma, Mohamed Jeljeli, Juan F Alzate, Felipe Cabarcas, Taushif Khan, Darawan Rinchai, Jean-Luc Prétet, Bertrand Boisson, Nico Marr, Ruba Ibrahim, Vered Molho-Pessach, Stéphanie Boisson-Dupuis, Dimitra Kiritsi, João T Barata, Nils Landegren, Bénédicte Neven, Laurent Abel, Andrea Lisco, Vivien Béziat, Emmanuelle Jouanguy, Jacinta Bustamante, James P Di Santo, Stuart G Tangye, Luigi D Notarangelo, Rémi Cheynier, Ken Natsuga, Andrés A Arias, José Luis Franco, Klaus Warnatz, Jean-Laurent Casanova, Anne Puel

Infants with biallelic IL7R loss-of-function variants have severe combined immune deficiency (SCID) characterized by the absence of autologous T lymphocytes, but normal counts of circulating B and NK cells (T-B+NK+ SCID). We report 6 adults (aged 22 to 59 years) from 4 kindreds and 3 ancestries (Colombian, Israeli Arab, Japanese) carrying homozygous IL7 loss-of-function variants resulting in combined immunodeficiency (CID). Deep immunophenotyping revealed relatively normal counts and/or proportions of myeloid, B, NK, and innate lymphoid cells. By contrast, the patients had profound T cell lymphopenia, with low proportions of innate-like adaptive mucosal-associated invariant T and invariant NK T cells. They also had low blood counts of T cell receptor (TCR) excision circles, recent thymic emigrant T cells and naive CD4+ T cells, and low overall TCR repertoire diversity, collectively indicating impaired thymic output. The proportions of effector memory CD4+ and CD8+ T cells were high, indicating IL-7-independent homeostatic T cell proliferation in the periphery. Intriguingly, the proportions of other T cell subsets, including TCRγδ+ T cells and some TCRαβ+ T cell subsets (including Th1, Tfh, and Treg) were little affected. Peripheral CD4+ T cells displayed poor proliferation, but normal cytokine production upon stimulation with mitogens in vitro. Thus, inherited IL-7 deficiency impairs T cell development less severely and in a more subset-specific manner than IL-7R deficiency. These findings suggest that another IL-7R-binding cytokine, possibly thymic stromal lymphopoietin, governs an IL-7-independent pathway of human T cell development.

携带双倍性 IL7R 功能缺失变体的婴儿具有严重的联合免疫缺陷症(SCID),其特征是缺乏自体 T 淋巴细胞,但循环 B 细胞和 NK 细胞数量正常(T-B+NK+ SCID)。我们报告了 6 名成年人(22 至 59 岁),他们来自 4 个血统和 3 个祖先(哥伦比亚人、以色列阿拉伯人和日本人),携带导致联合免疫缺陷症(CID)的同基因 IL7 功能缺失变体。深度免疫分型显示,骨髓细胞、B细胞、NK细胞和先天性淋巴细胞的数量和/或比例相对正常。相比之下,患者有严重的 T 细胞淋巴细胞减少症,先天类适应性粘膜相关不变 T 细胞和不变 NK T 细胞比例较低。他们血液中的T细胞受体(TCR)切割圈、新近胸腺移出的T细胞和幼稚CD4+T细胞的数量也很低,而且总体TCR库的多样性也很低,这共同表明胸腺输出受损。效应记忆 CD4+ 和 CD8+ T 细胞的比例较高,表明外周存在不依赖于 IL-7 的同源性 T 细胞增殖。有趣的是,其他T细胞亚群的比例,包括TCRγδ+ T细胞和一些TCRαβ+ T细胞亚群(包括Th1、Tfh和Treg)几乎没有受到影响。外周 CD4+ T 细胞增殖不良,但在体外有丝分裂原刺激下细胞因子的产生正常。因此,与 IL-7R 缺乏症相比,遗传性 IL-7 缺乏症对 T 细胞发育的损害不那么严重,而且亚群特异性更强。这些发现表明,另一种与IL-7R结合的细胞因子(可能是胸腺基质淋巴细胞生成素)支配着人类T细胞发育的一条与IL-7无关的途径。
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引用次数: 0
Reciprocal regulation by TLR4 and TGF-β in tumor-initiating stem-like cells. TLR4 和 TGF-β 在肿瘤诱导干样细胞中的相互调控。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 DOI: 10.1172/JCI186923
Chia-Lin Chen, Hidekazu Tsukamoto, Jian-Chang Liu, Claudine Kashiwabara, Douglas Feldman, Linda Sher, Steven Dooley, Samuel W French, Lopa Mishra, Lydia Petrovic, Joseph H Jeong, Keigo Machida
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引用次数: 0
IFN-γ and YAP lead epithelial cells astray after severe respiratory infection. 严重呼吸道感染后,IFN-γ 和 YAP 将上皮细胞引入歧途。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-10-01 DOI: 10.1172/JCI185072
Bradley E Hiller, Joseph P Mizgerd

Ineffective recovery from pneumonia can lead to interstitial lung disease characterized by aberrant epithelial cells in fibrotic regions. In this issue of the JCI, Lin et al. define molecular pathways leading to the development and persistence of keratin 5+ (Krt5+) epithelial cells in the alveolar parenchyma when mice struggle to recover from influenza infection. The receptor for IFN-γ on lung epithelium was essential for the formation of aberrant Krt5+ cells and fibrotic lung disease. The transcription factor Yes-associated protein 1 (YAP) was necessary for persistence of these Krt5+ cells, and IFN-γ activated YAP in lung epithelial cells via JAK, focal adhesion kinase (FAK), and Src kinases. These findings establish a targetable pathway underlying some of the pulmonary postacute sequelae of pneumonia.

肺炎恢复不佳会导致间质性肺病,其特征是纤维化区域出现异常上皮细胞。在本期 JCI 杂志上,Lin 等人明确了当小鼠从流感感染中挣扎着恢复时,导致角蛋白 5+(Krt5+)上皮细胞在肺泡实质中发育和持续存在的分子途径。肺上皮细胞上的IFN-γ受体对异常Krt5+细胞的形成和肺纤维化疾病至关重要。转录因子Yes相关蛋白1(YAP)是这些Krt5+细胞持续存在的必要条件,IFN-γ通过JAK、局灶粘附激酶(FAK)和Src激酶激活肺上皮细胞中的YAP。这些发现为肺炎急性后遗症的某些肺部病变提供了一个靶向途径。
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引用次数: 0
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