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B cell-based therapy produces antibodies that inhibit glioblastoma growth. 基于 B 细胞的疗法能产生抑制胶质母细胞瘤生长的抗体。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-08-29 DOI: 10.1172/JCI177384
Si Wang, Brandyn A Castro, Joshua L Katz, Victor Arrieta, Hinda Najem, Gustavo I Vazquez-Cervantes, Hanxiao Wan, Ian E Olson, David Hou, Mark Dapash, Leah K Billingham, Tzu-Yi Chia, Chao Wei, Aida Rashidi, Leonidas C Platanias, Kathleen McCortney, Craig M Horbinski, Roger Stupp, Peng Zhang, Atique U Ahmed, Adam M Sonabend, Amy B Heimberger, Maciej S Lesniak, Cécile Riviere-Cazaux, Terry Burns, Jason Miska, Mariafausta Fischietti, Catalina Lee-Chang

Glioblastoma (GBM) is a highly aggressive and malignant brain tumor with limited therapeutic options and a poor prognosis. Despite current treatments, the invasive nature of GBM often leads to recurrence. A promising alternative strategy is to harness the potential of the immune system against tumor cells. Our previous data showed that the BVax (B cell-based vaccine) can induce therapeutic responses in preclinical models of GBM. In this study, we aimed to characterize the antigenic reactivity of BVax-derived Abs and evaluate their therapeutic potential. We performed immunoproteomics and functional assays in murine models and samples from patients with GBM. Our investigations revealed that BVax distributed throughout the GBM tumor microenvironment and then differentiated into Ab-producing plasmablasts. Proteomics analyses indicated that the Abs produced by BVax had unique reactivity, predominantly targeting factors associated with cell motility and the extracellular matrix. Crucially, these Abs inhibited critical processes such as GBM cell migration and invasion. These findings provide valuable insights into the therapeutic potential of BVax-derived Abs for patients with GBM, pointing toward a novel direction for GBM immunotherapy.

胶质母细胞瘤(GBM)是一种侵袭性极强的恶性脑肿瘤,治疗手段有限,预后较差。尽管目前有多种治疗方法,但 GBM 的侵袭性往往导致复发。利用免疫系统的潜力来对抗肿瘤细胞是一种很有前景的替代策略。我们之前的数据显示,Bvax(基于 B 细胞的疫苗)可以在 GBM 临床前模型中诱导治疗反应。在本研究中,我们旨在描述 BVax 衍生抗体的抗原反应性并评估其治疗潜力。我们在小鼠模型和人类 GBM 患者样本中进行了免疫蛋白组学和功能测定。我们的研究发现,BVax分布在整个GBM肿瘤微环境(TME)中,然后分化成产生抗体的浆细胞。蛋白质组分析表明,BVax 产生的抗体具有独特的反应性,主要靶向与细胞运动和细胞外基质相关的因子。最重要的是,这些抗体能抑制 GBM 细胞迁移和侵袭等关键过程。这些发现为 BVax 衍生抗体对 GBM 患者的治疗潜力提供了宝贵的见解,为 GBM 免疫疗法指明了新的方向。
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引用次数: 0
Deciphering bone marrow engraftment after allogeneic stem cell transplantation in humans using single-cell analyses. 利用单细胞分析解密人类异体干细胞移植后的骨髓移植。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-08-29 DOI: 10.1172/JCI180331
Jennifer Bordenave, Dorota Gajda, David Michonneau, Nicolas Vallet, Mathieu Chevalier, Emmanuelle Clappier, Pierre Lemaire, Stéphanie Mathis, Marie Robin, Aliénor Xhaard, Flore Sicre de Fontbrune, Aurélien Corneau, Sophie Caillat-Zucman, Regis Peffault de Latour, Emmanuel Curis, Gérard Socié

BACKGROUNDDonor cell engraftment is a prerequisite of successful allogeneic hematopoietic stem cell transplantation. Based on peripheral blood analyses, it is characterized by early myeloid recovery and T and B cell lymphopenia. However, cellular networks associated with bone marrow engraftment of allogeneic human cells have been poorly described.METHODSMass cytometry and CITE-Seq analyses were performed on bone marrow cells 3 months after transplantation in patients with acute myelogenous leukemia.RESULTSMass cytometric analyses in 26 patients and 20 healthy controls disclosed profound alterations in myeloid and B cell progenitors, with a shift toward terminal myeloid differentiation and decreased B cell progenitors. Unsupervised analysis separated recipients into 2 groups, one of them being driven by previous graft-versus-host disease (R2 patients). We then used single-cell CITE-Seq to decipher engraftment, which resolved 36 clusters, encompassing all bone marrow cellular components. Hematopoiesis in transplant recipients was sustained by committed myeloid and erythroid progenitors in a setting of monocyte-, NK cell-, and T cell-mediated inflammation. Gene expression revealed major pathways in transplant recipients, namely, TNF-α signaling via NF-κB and the IFN-γ response. The hallmark of allograft rejection was consistently found in clusters from transplant recipients, especially in R2 recipients.CONCLUSIONBone marrow cell engraftment of allogeneic donor cells is characterized by a state of emergency hematopoiesis in the setting of an allogeneic response driving inflammation.FUNDINGThis study was supported by the French National Cancer Institute (Institut National du Cancer; PLBIO19-239) and by an unrestricted research grant by Alexion Pharmaceuticals.

背景:供体细胞移植是异基因造血干细胞移植成功的前提条件。根据外周血分析,其特点是骨髓早期恢复以及 T 细胞和 B 细胞淋巴细胞减少。然而,与异体人体细胞骨髓移植相关的细胞网络却鲜有描述:方法:对急性髓性白血病患者移植后三个月的骨髓细胞进行了质粒计数和 CITEseq 分析:结果:对 26 名患者和 20 名健康对照者进行的质细胞术显示,髓细胞和 B 细胞祖细胞发生了深刻变化,髓细胞向末端分化转变,B 细胞祖细胞减少。无监督分析将受试者分为两组,其中一组是由既往 GVHD 引起的(R2 患者)。然后,我们使用单细胞 CITEseq 对移植进行解密,发现了 36 个集群,涵盖了所有骨髓细胞成分。在单核细胞、NK 细胞和 T 细胞介导的炎症环境中,移植受者的造血是由髓系和红系祖细胞维持的。基因表达揭示了移植受者的主要通路,即通过 NFκ-B 的 TNFα 信号和干扰素-γ 反应。在移植受者的集群中,尤其是在R2受者中,持续发现了异体移植排斥反应的特征:结论:异体供体细胞的骨髓细胞移植特点是在异体反应驱动炎症的情况下的紧急造血状态:不适用:本研究得到了法国国家癌症研究所(Institut National du Cancer)的支持:PLBIO19-239和Alexion Pharmaceutical的无限制研究基金。
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引用次数: 0
West Nile virus triggers intestinal dysmotility via T cell-mediated enteric nervous system injury. 西尼罗河病毒通过 T 细胞介导的肠神经系统损伤引发肠道运动障碍。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-08-29 DOI: 10.1172/JCI181421
Hana Janova, Fang R Zhao, Pritesh Desai, Matthias Mack, Larissa B Thackray, Thaddeus S Stappenbeck, Michael S Diamond

Intestinal dysmotility syndromes have been epidemiologically associated with several antecedent bacterial and viral infections. To model this phenotype, we previously infected mice with the neurotropic flavivirus West Nile virus (WNV) and demonstrated intestinal transit defects. Here, we found that within 1 week of WNV infection, enteric neurons and glia became damaged, resulting in sustained reductions of neuronal cells and their networks of connecting fibers. Using cell-depleting antibodies, adoptive transfer experiments, and mice lacking specific immune cells or immune functions, we show that infiltrating WNV-specific CD4+ and CD8+ T cells damaged the enteric nervous system (ENS) and glia, which led to intestinal dysmotility; these T cells used multiple and redundant effector molecules including perforin and Fas ligand. In comparison, WNV-triggered ENS injury and intestinal dysmotility appeared to not require infiltrating monocytes, and damage may have been limited by resident muscularis macrophages. Overall, our experiments support a model in which antigen-specific T cell subsets and their effector molecules responding to WNV infection direct immune pathology against enteric neurons and supporting glia that results in intestinal dysmotility.

从流行病学角度看,肠道运动障碍综合征与几种先驱细菌和病毒感染有关。为了模拟这种表型,我们曾用具有神经毒性的黄病毒--西尼罗河病毒(WNV)感染小鼠,结果显示小鼠出现肠道转运缺陷。在这里,我们发现在感染西尼罗河病毒一周内,肠道神经元和胶质细胞受损,导致神经元细胞及其连接纤维网络持续减少。利用细胞清除抗体、收养性转移实验和缺乏特异性免疫细胞或免疫功能的小鼠,我们发现浸润的 WNV 特异性 CD4+ 和 CD8+ T 细胞会损伤肠神经系统(ENS)和神经胶质,从而导致肠道运动障碍;这些 T 细胞使用了多种冗余效应功能,包括穿孔素和 Fas 配体。相比之下,WNV 触发的 ENS 损伤和肠道运动障碍似乎不需要浸润的单核细胞,而且损伤可能受到常驻肌层巨噬细胞的限制。总之,我们的实验支持这样一种模式,即抗原特异性 T 细胞亚群及其效应分子对 WNV 感染做出反应,直接对肠道神经元和支持神经胶质产生免疫病理学作用,从而导致肠道运动障碍。
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引用次数: 0
Retinal perivascular macrophages regulate immune cell infiltration during neuroinflammation in mouse models of ocular disease. 视网膜血管周围巨噬细胞在眼疾小鼠模型的神经炎症过程中调节免疫细胞浸润。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-08-29 DOI: 10.1172/JCI180904
Jacob K Sterling, Amrita Rajesh, Steven Droho, Joyce Gong, Andrew L Wang, Andrew P Voigt, C Elysse Brookins, Jeremy A Lavine

The blood-retina barrier (BRB), which is disrupted in diabetic retinopathy (DR) and uveitis, is an important anatomical characteristic of the retina, regulating nutrient, waste, water, protein, and immune cell flux. The BRB is composed of endothelial cell tight junctions, pericytes, astrocyte end feet, a collagen basement membrane, and perivascular macrophages. Despite the importance of the BRB, retinal perivascular macrophage function remains unknown. We found that retinal perivascular macrophages resided on postcapillary venules in the superficial vascular plexus and expressed MHC class II. Using single-cell RNA-Seq, we found that perivascular macrophages expressed a prochemotactic transcriptome and identified platelet factor 4 (Pf4, also known as CXCL4) as a perivascular macrophage marker. We used Pf4Cre mice to specifically deplete perivascular macrophages. To model retinal inflammation, we performed intraocular CCL2 injections. Ly6C+ monocytes crossed the BRB proximal to perivascular macrophages. Depletion of perivascular macrophages severely hampered Ly6C+ monocyte infiltration. These data suggest that retinal perivascular macrophages orchestrate immune cell migration across the BRB, with implications for inflammatory ocular diseases including DR and uveitis.

在糖尿病视网膜病变(DR)和葡萄膜炎中被破坏的血-视网膜屏障(BRB)是视网膜的一个重要解剖特征,它调节着营养物质、废物、水、蛋白质和免疫细胞的流动。BRB由内皮细胞紧密连接、周细胞、星形胶质细胞端足、胶原基底膜和血管周围巨噬细胞组成。尽管BRB非常重要,但视网膜血管周围巨噬细胞的功能仍然未知。我们发现,视网膜血管周围巨噬细胞驻留在浅层血管丛中的毛细血管后静脉上,并表达 MHCII。通过单细胞 RNA 测序,我们发现血管周围巨噬细胞表达一种促趋化转录组,并确定 Pf4/CXCL4 为血管周围巨噬细胞标记。我们利用 Pf4Cre 小鼠特异性地清除血管周围巨噬细胞。为了模拟视网膜炎症,我们在眼内注射了 CCL2。Ly6C+单核细胞穿过BRB,接近血管周围巨噬细胞。血管周围巨噬细胞的耗竭严重阻碍了 Ly6C+ 单核细胞的浸润。这些数据表明,视网膜血管周围巨噬细胞可协调免疫细胞穿过 BRB 的迁移,这对包括 DR 和葡萄膜炎在内的炎症性眼病具有重要意义。
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引用次数: 0
Parkin activates innate immunity and promotes anti-tumor immune responses. 帕金激活先天性免疫,促进抗肿瘤免疫反应。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-08-29 DOI: 10.1172/JCI180983
Michela Perego, Minjeong Yeon, Ekta Agarwal, Andrew T Milcarek, Irene Bertolini, Chiara Camisaschi, Jagadish C Ghosh, Hsin-Yao Tang, Nathalie Grandvaux, Marcus Ruscetti, Andrew V Kossenkov, Sarah Preston-Alp, Italo Tempera, Noam Auslander, Dario C Altieri

The activation of innate immunity and associated interferon (IFN) signaling have been implicated in cancer, but the regulators are elusive and a link to tumor suppression undetermined. Here, we found that Parkin, an E3 ubiquitin ligase altered in Parkinson's Disease was epigenetically silenced in cancer and its re-expression by clinically approved demethylating therapy stimulated transcription of a potent IFN response in tumor cells. This pathway required Parkin E3 ubiquitin ligase activity, involved the subcellular trafficking and release of the alarmin High Mobility Group Box 1 (HMGB1) and was associated with inhibition of NFκB gene expression. In turn, Parkin-expressing cells released an IFN secretome that upregulated effector and cytotoxic CD8 T cell markers, lowered the expression of immune inhibitory receptors, TIM3 and LAG3, and stimulated high content of the self-renewal/stem cell factor, TCF1. Parkin-induced CD8 T cells selectively accumulated in the microenvironment and inhibited transgenic and syngeneic tumor growth, in vivo. Therefore, Parkin is an epigenetically regulated activator of innate immunity and dual mode tumor suppressor, inhibiting intrinsic tumor traits of metabolism and cell invasion, while simultaneously reinvigorating CD8 T cell functions in the microenvironment.

先天性免疫的激活和相关的干扰素(IFN)信号传导与癌症有牵连,但调节因素难以捉摸,与肿瘤抑制的联系也未确定。在这里,我们发现在帕金森病中发生改变的E3泛素连接酶Parkin在癌症中被表观遗传沉默,而通过临床认可的去甲基化疗法重新表达Parkin可刺激肿瘤细胞转录强效的IFN反应。这一途径需要Parkin E3泛素连接酶的活性,涉及警戒素高迁移率组盒1(HMGB1)的亚细胞迁移和释放,并与抑制NFκB基因表达有关。反过来,表达 Parkin 的细胞释放 IFN 分泌组,上调效应和细胞毒性 CD8 T 细胞标记物,降低免疫抑制受体 TIM3 和 LAG3 的表达,并刺激自我更新/干细胞因子 TCF1 的高含量。Parkin 诱导的 CD8 T 细胞选择性地在微环境中积累,并抑制转基因和合成肿瘤的体内生长。因此,Parkin 是一种受表观遗传调控的先天性免疫激活因子和双模式肿瘤抑制因子,可抑制肿瘤内在的新陈代谢和细胞侵袭特性,同时重振微环境中 CD8 T 细胞的功能。
{"title":"Parkin activates innate immunity and promotes anti-tumor immune responses.","authors":"Michela Perego, Minjeong Yeon, Ekta Agarwal, Andrew T Milcarek, Irene Bertolini, Chiara Camisaschi, Jagadish C Ghosh, Hsin-Yao Tang, Nathalie Grandvaux, Marcus Ruscetti, Andrew V Kossenkov, Sarah Preston-Alp, Italo Tempera, Noam Auslander, Dario C Altieri","doi":"10.1172/JCI180983","DOIUrl":"10.1172/JCI180983","url":null,"abstract":"<p><p>The activation of innate immunity and associated interferon (IFN) signaling have been implicated in cancer, but the regulators are elusive and a link to tumor suppression undetermined. Here, we found that Parkin, an E3 ubiquitin ligase altered in Parkinson's Disease was epigenetically silenced in cancer and its re-expression by clinically approved demethylating therapy stimulated transcription of a potent IFN response in tumor cells. This pathway required Parkin E3 ubiquitin ligase activity, involved the subcellular trafficking and release of the alarmin High Mobility Group Box 1 (HMGB1) and was associated with inhibition of NFκB gene expression. In turn, Parkin-expressing cells released an IFN secretome that upregulated effector and cytotoxic CD8 T cell markers, lowered the expression of immune inhibitory receptors, TIM3 and LAG3, and stimulated high content of the self-renewal/stem cell factor, TCF1. Parkin-induced CD8 T cells selectively accumulated in the microenvironment and inhibited transgenic and syngeneic tumor growth, in vivo. Therefore, Parkin is an epigenetically regulated activator of innate immunity and dual mode tumor suppressor, inhibiting intrinsic tumor traits of metabolism and cell invasion, while simultaneously reinvigorating CD8 T cell functions in the microenvironment.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":null,"pages":null},"PeriodicalIF":13.3,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142107935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Proton-activated chloride channel increases endplate porosity and pain in a mouse spine degeneration model. 质子激活的氯离子通道可增加小鼠脊柱退化模型的终板孔隙度和疼痛。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-08-28 DOI: 10.1172/JCI168155
Peng Xue, Weixin Zhang, Mengxi Shen, Junhua Yang, Jiachen Chu, Shenyu Wang, Mei Wan, Junying Zheng, Zhaozhu Qiu, Xu Cao

Chronic low back pain (LBP) can severely affect daily physical activity. Aberrant osteoclast-mediated resorption leads to porous endplates, which allow the sensory innervation that causes LBP. Here, we report that expression of the proton-activated chloride (PAC) channel was induced during osteoclast differentiation in the porous endplates via a RANKL/NFATc1 signaling pathway. Extracellular acidosis evoked robust PAC currents in osteoclasts. An acidic environment of porous endplates and elevated PAC activation-enhanced osteoclast fusion provoked LBP. Furthermore, we found that genetic knockout of the PAC gene Pacc1 significantly reduced endplate porosity and spinal pain in a mouse LBP model, but it did not affect bone development or homeostasis of bone mass in adult mice. Moreover, both the osteoclast bone-resorptive compartment environment and PAC traffic from the plasma membrane to endosomes to form an intracellular organelle Cl channel had a low pH of approximately 5.0. The low pH environment activated the PAC channel to increase sialyltransferase St3gal1 expression and sialylation of TLR2 in the initiation of osteoclast fusion. Aberrant osteoclast-mediated resorption is also found in most skeletal disorders, including osteoarthritis, ankylosing spondylitis, rheumatoid arthritis, heterotopic ossification, and enthesopathy. Thus, elevated Pacc1 expression and PAC activity could be a potential therapeutic target for the treatment of LBP and osteoclast-associated pain.

慢性腰背痛(LBP)会严重影响日常体力活动。破骨细胞介导的异常吸收导致多孔内板的感觉神经支配,从而引起腰背痛。在此,我们报告了破骨细胞在多孔内板分化过程中通过 RANKL-NFATc1 信号通路诱导质子激活氯化物(PAC)通道的表达。细胞外酸中毒会在破骨细胞中唤起强大的 PAC 电流。多孔内板的酸性环境和升高的 PAC 激活增强的破骨细胞融合引发了枸杞多糖。此外,我们还发现,在小鼠枸杞痛模型中,基因敲除 PAC 基因 Pacc1 可显著降低终板多孔性和脊柱疼痛,但不会影响成年小鼠的骨骼发育或骨量平衡。此外,破骨细胞骨吸收区环境和 PAC 从质膜到内质体形成细胞内细胞器 Cl 通道的过程都具有 5.0 左右的低 pH 值。低pH环境激活了PAC通道,增加了硅氨基转移酶St3gal1的表达和TLR2的硅氨基化,从而启动了破骨细胞的融合。破骨细胞介导的异常吸收也存在于大多数骨骼疾病中,包括骨关节炎、强直性脊柱炎、类风湿性关节炎、异位骨化和骨关节病。因此,Pacc1 表达和 PAC 活性的升高可能是枸杞痛和破骨细胞相关疼痛的潜在治疗靶点。
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引用次数: 0
Quantifying variant contributions in cystic kidney disease using national-scale whole-genome sequencing. 利用全国范围的全基因组测序量化囊性肾病的变异贡献。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-08-27 DOI: 10.1172/JCI181467
Omid Sadeghi-Alavijeh, Melanie My Chan, Gabriel T Doctor, Catalin D Voinescu, Alexander Stuckey, Athanasios Kousathanas, Alexander T Ho, Horia C Stanescu, Detlef Bockenhauer, Richard N Sandford, Adam P Levine, Daniel P Gale

BACKGROUNDCystic kidney disease (CyKD) is a predominantly familial disease in which gene discovery has been led by family-based and candidate gene studies, an approach that is susceptible to ascertainment and other biases.METHODSUsing whole-genome sequencing data from 1,209 cases and 26,096 ancestry-matched controls participating in the 100,000 Genomes Project, we adopted hypothesis-free approaches to generate quantitative estimates of disease risk for each genetic contributor to CyKD, across genes, variant types and allelic frequencies.RESULTSIn 82.3% of cases, a qualifying potentially disease-causing rare variant in an established gene was found. There was an enrichment of rare coding, splicing, and structural variants in known CyKD genes, with statistically significant gene-based signals in COL4A3 and (monoallelic) PKHD1. Quantification of disease risk for each gene (with replication in the separate UK Biobank study) revealed substantially lower risk associated with genes more recently associated with autosomal dominant polycystic kidney disease, with odds ratios for some below what might usually be regarded as necessary for classical Mendelian inheritance. Meta-analysis of common variants did not reveal significant associations, but suggested this category of variation contributes 3%-9% to the heritability of CyKD across European ancestries.CONCLUSIONBy providing unbiased quantification of risk effects per gene, this research suggests that not all rare variant genetic contributors to CyKD are equally likely to manifest as a Mendelian trait in families. This information may inform genetic testing and counseling in the clinic.

背景囊性肾脏病(CyKD)是一种以家族性为主的疾病,其基因发现主要是基于家族和候选基因的研究,这种方法容易受到确定性和其他偏倚的影响。方法利用参与 10 万基因组计划的 1209 例病例和 26096 例祖先匹配对照的全基因组测序数据,我们采用了无假设方法,对 CyKD 的每个遗传因素、不同基因、变异类型和等位基因频率进行了疾病风险的定量估计。在已知的CyKD基因中,罕见编码、剪接和结构变异丰富,在COL4A3和(单等位基因)PKHD1中发现了具有统计学意义的新基因信号。对每个基因的疾病风险进行量化(在单独的英国生物库研究中复制)显示,最近与常染色体显性多囊肾病相关的基因的风险大大降低,其中一些基因的几率比低于通常被认为是经典孟德尔遗传所必需的几率比。通过对每个基因的风险效应进行无偏量化,这项研究表明,并非所有导致 CyKD 的罕见变异基因都同样可能在家族中表现为孟德尔性状。关键词:基因组学;囊性肾病;肾脏;ADPKD;WGS。
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引用次数: 0
The senescence-associated secretome of Hedgehog-deficient hepatocytes drives MASLD progression. 刺猬缺陷型肝细胞的衰老相关分泌组推动了 MASLD 的进展。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-08-27 DOI: 10.1172/JCI180310
Ji Hye Jun, Kuo Du, Rajesh Kumar Dutta, Raquel Maeso-Diaz, Seh Hoon Oh, Liuyang Wang, Guannan Gao, Ana Ferreira, Jon Hill, Steven S Pullen, Anna Mae Diehl

The burden of senescent hepatocytes correlates with the severity of metabolic dysfunction-associated steatotic liver disease (MASLD), but the mechanisms driving senescence and how it exacerbates MASLD are poorly understood. Hepatocytes experience lipotoxicity and become senescent when Smoothened (Smo) is deleted to disrupt Hedgehog signaling. We aimed to determine whether the secretomes of Smo-deficient hepatocytes perpetuate senescence to drive MASLD progression. RNA-Seq analysis of liver samples from human and murine cohorts with MASLD confirmed that hepatocyte populations in MASLD livers were depleted of Smo+ cells and enriched with senescent cells. When fed a choline-deficient, amino acid-restricted high-fat diet (CDA-HFD) to induce MASLD, Smo- mice had lower antioxidant markers and developed worse DNA damage, senescence, steatohepatitis, and fibrosis than did Smo+ mice. Sera and hepatocyte-conditioned medium from Smo- mice were depleted of thymidine phosphorylase (TP), a protein that maintains mitochondrial fitness. Treating Smo- hepatocytes with TP reduced senescence and lipotoxicity, whereas inhibiting TP in Smo+ hepatocytes had the opposite effect and exacerbated hepatocyte senescence, steatohepatitis, and fibrosis in CDA-HFD-fed mice. We conclude that inhibition of Hedgehog signaling in hepatocytes promoted MASLD by suppressing hepatocyte production of proteins that prevent lipotoxicity and senescence.

衰老肝细胞的负担与 MASLD 的严重程度相关,但人们对衰老的驱动机制以及衰老如何加剧 MASLD 还知之甚少。当删除 Smoothened(Smo)以破坏刺猬信号传导时,肝细胞就会衰老。我们的目的是确定 Smo 缺陷肝细胞的分泌组是否会延续衰老,从而推动 MASLD 的进展。RNA seq分析证实,MASLD肝脏的肝细胞群中缺少Smo(+)细胞,而富含衰老细胞。与Smo(+)小鼠相比,喂食CDA-HFD的Smo(-)小鼠的抗氧化标志物更低,DNA损伤、衰老、MASH和肝纤维化的情况更严重。Smo(-)小鼠的血清和肝细胞调节培养基中的胸苷磷酸化酶(TP)被耗尽,而胸苷磷酸化酶是一种维持线粒体健康的蛋白质。用 TP 处理 Smo(-)肝细胞可减少衰老和脂肪毒性;抑制 Smo(+)肝细胞中的 TP 则会产生相反的效果,并加剧 CDA-HFD 喂养小鼠的肝细胞衰老、MASH 和纤维化。因此,我们发现抑制肝细胞中的刺猬信号传导会抑制肝细胞产生防止脂肪毒性和衰老的蛋白质,从而促进 MASLD。
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引用次数: 0
Single-cell multiomic analysis identifies macrophage subpopulations in promoting cardiac repair. 单细胞多组学分析确定了促进心脏修复的巨噬细胞亚群。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-08-27 DOI: 10.1172/JCI175297
Mingzhu Fu, Shengtao Jia, Longhui Xu, Xin Li, Yufang Lv, Yulong Zhong, Shanshan Ai

Cardiac mononuclear phagocytic cells (Cardiac MPCs) participate in maintaining homeostasis and orchestrating cardiac responses upon injury. However, the function of specific MPC subtypes and the related cell fate commitment mechanisms remain elusive in regenerative and nonregenerative hearts due to their cellular heterogeneities. Using spatiotemporal single-cell epigenomic analysis of cardiac MPCs in regenerative (P1) and nonregenerative (P10) mouse hearts after injury, we found that P1 hearts accumulate reparative Arg1+ macrophages, while proinflammatory S100a9+Ly6c+ monocytes are uniquely abundant during nonregenerative remodeling. Moreover, blocking chemokine CXCR2 to inhibit the specification of the S100a9+Ly6c+-biased inflammatory fate in P10 hearts resulted in elevated wound repair responses and marked improvements in cardiac function after injury. Single-cell RNA-Seq further confirmed an increased Arg1+ macrophage subpopulation after CXCR2 blockade, which was accomplished by increased expression of wound repair-related genes and reduced expression of proinflammatory genes. Collectively, our findings provide instructive insights into the molecular mechanisms underlying the function and fate specification of heterogeneous MPCs during cardiac repair and identify potential therapeutic targets for myocardial infarction.

心脏巨噬细胞/单核细胞参与维持稳态和协调损伤时的心脏反应。然而,由于再生性和非再生性心脏的细胞异质性,特定巨噬细胞/单核细胞亚型的功能和相关的细胞命运承诺机制仍然难以捉摸。通过对损伤后再生性(P1)和非再生性(P10)小鼠心脏中的巨噬细胞/单核细胞进行时空单细胞表观组学分析,我们发现 P1 心脏中积累了修复性 Arg1+ 巨噬细胞,而促炎性 S100a9+Ly6c+ 单核细胞在非再生性重塑过程中异常丰富。此外,阻断趋化因子 CXCR2 以抑制 P10 心脏中 S100a9+Ly6c+ 偏向炎症命运的规范化,可提高伤口修复反应,明显改善损伤后的心脏功能。单细胞 RNA 片段分析进一步证实,CXCR2 受体阻断后,Arg1+ 巨噬细胞亚群增加,伤口修复相关基因表达增加,促炎基因表达减少。总之,我们的研究结果为了解心脏修复过程中异质巨噬细胞/单核细胞的功能和命运分化的分子机制提供了启发,并确定了心肌梗死的潜在治疗靶点。
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引用次数: 0
Spatiotemporal transcriptomic mapping of regenerative inflammation in skeletal muscle reveals a dynamic multilayered tissue architecture. 骨骼肌再生炎症的时空转录组图谱揭示了动态多层组织结构。
IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-08-27 DOI: 10.1172/JCI173858
Andreas Patsalos, Laszlo Halasz, Darby Oleksak, Xiaoyan Wei, Gergely Nagy, Petros Tzerpos, Thomas Conrad, David W Hammers, H Lee Sweeney, Laszlo Nagy

Tissue regeneration is orchestrated by macrophages that clear damaged cells and promote regenerative inflammation. How macrophages spatially adapt and diversify their functions to support the architectural requirements of actively regenerating tissue remains unknown. In this study, we reconstructed the dynamic trajectories of myeloid cells isolated from acutely injured and early stage dystrophic muscles. We identified divergent subsets of monocytes/macrophages and DCs and validated markers (e.g., glycoprotein NMB [GPNMB]) and transcriptional regulators associated with defined functional states. In dystrophic muscle, specialized repair-associated subsets exhibited distinct macrophage diversity and reduced DC heterogeneity. Integrating spatial transcriptomics analyses with immunofluorescence uncovered the ordered distribution of subpopulations and multilayered regenerative inflammation zones (RIZs) where distinct macrophage subsets are organized in functional zones around damaged myofibers supporting all phases of regeneration. Importantly, intermittent glucocorticoid treatment disrupted the RIZs. Our findings suggest that macrophage subtypes mediated the development of the highly ordered architecture of regenerative tissues, unveiling the principles of the structured yet dynamic nature of regenerative inflammation supporting effective tissue repair.

组织再生是由巨噬细胞协调的,巨噬细胞清除受损细胞并促进再生炎症。巨噬细胞如何在空间上适应并多样化其功能,以支持活跃再生组织的结构要求,目前仍是未知数。在这项研究中,我们重建了从急性损伤和早期萎缩性肌肉中分离出来的髓样细胞的动态轨迹。我们确定了单核细胞/巨噬细胞和树突状细胞(DCs)的不同亚群,并验证了与确定的功能状态相关的标记物(如 GPNMB)和转录调节因子。在萎缩性肌肉中,特化的修复相关亚群表现出独特的巨噬细胞多样性和减少的DC异质性。将空间转录组学分析与免疫荧光相结合,发现了巨噬细胞亚群的有序分布和多层再生炎症区(RIZs),其中不同的巨噬细胞亚群组织在受损肌纤维周围的功能区,支持再生的所有阶段。重要的是,间歇性糖皮质激素治疗会破坏再生炎症区。我们的研究结果表明,巨噬细胞亚型介导了再生组织高度有序结构的发展,揭示了支持有效组织修复的再生炎症的结构性和动态性原理。
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Journal of Clinical Investigation
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