Journal of Clinical Investigation最新文献

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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
Journal of Clinical Investigation 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
{"title":"B cell-based therapy produces antibodies that inhibit glioblastoma growth.","authors":"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","doi":"10.1172/JCI177384","DOIUrl":"10.1172/JCI177384","url":null,"abstract":"<p><p>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.</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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11473152/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142107932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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
Journal of Clinical Investigation 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
{"title":"Deciphering bone marrow engraftment after allogeneic stem cell transplantation in humans using single-cell analyses.","authors":"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","doi":"10.1172/JCI180331","DOIUrl":"10.1172/JCI180331","url":null,"abstract":"<p><p>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.</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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11473149/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142107933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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
Journal of Clinical Investigation 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
{"title":"West Nile virus triggers intestinal dysmotility via T cell-mediated enteric nervous system injury.","authors":"Hana Janova, Fang R Zhao, Pritesh Desai, Matthias Mack, Larissa B Thackray, Thaddeus S Stappenbeck, Michael S Diamond","doi":"10.1172/JCI181421","DOIUrl":"10.1172/JCI181421","url":null,"abstract":"<p><p>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.</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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11527448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142107937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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
Journal of Clinical Investigation 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
{"title":"Retinal perivascular macrophages regulate immune cell infiltration during neuroinflammation in mouse models of ocular disease.","authors":"Jacob K Sterling, Amrita Rajesh, Steven Droho, Joyce Gong, Andrew L Wang, Andrew P Voigt, C Elysse Brookins, Jeremy A Lavine","doi":"10.1172/JCI180904","DOIUrl":"10.1172/JCI180904","url":null,"abstract":"<p><p>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.</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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11473146/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142107936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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
Journal of Clinical Investigation 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
{"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
Journal of Clinical Investigation 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
{"title":"Proton-activated chloride channel increases endplate porosity and pain in a mouse spine degeneration model.","authors":"Peng Xue, Weixin Zhang, Mengxi Shen, Junhua Yang, Jiachen Chu, Shenyu Wang, Mei Wan, Junying Zheng, Zhaozhu Qiu, Xu Cao","doi":"10.1172/JCI168155","DOIUrl":"10.1172/JCI168155","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":null,"pages":null},"PeriodicalIF":13.3,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11473161/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142086052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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
Journal of Clinical Investigation 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
{"title":"Quantifying variant contributions in cystic kidney disease using national-scale whole-genome sequencing.","authors":"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","doi":"10.1172/JCI181467","DOIUrl":"10.1172/JCI181467","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":null,"pages":null},"PeriodicalIF":13.3,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11444187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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
Journal of Clinical Investigation 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
{"title":"The senescence-associated secretome of Hedgehog-deficient hepatocytes drives MASLD progression.","authors":"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","doi":"10.1172/JCI180310","DOIUrl":"10.1172/JCI180310","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":null,"pages":null},"PeriodicalIF":13.3,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11444248/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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
Journal of Clinical Investigation Pub Date : 2024-08-27 DOI: 10.1172/JCI175297
Mingzhu Fu, Shengtao Jia, Longhui Xu, Xin Li, Yufang Lv, Yulong Zhong, Shanshan Ai
{"title":"Single-cell multiomic analysis identifies macrophage subpopulations in promoting cardiac repair.","authors":"Mingzhu Fu, Shengtao Jia, Longhui Xu, Xin Li, Yufang Lv, Yulong Zhong, Shanshan Ai","doi":"10.1172/JCI175297","DOIUrl":"10.1172/JCI175297","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":null,"pages":null},"PeriodicalIF":13.3,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11444165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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
Journal of Clinical Investigation 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
{"title":"Spatiotemporal transcriptomic mapping of regenerative inflammation in skeletal muscle reveals a dynamic multilayered tissue architecture.","authors":"Andreas Patsalos, Laszlo Halasz, Darby Oleksak, Xiaoyan Wei, Gergely Nagy, Petros Tzerpos, Thomas Conrad, David W Hammers, H Lee Sweeney, Laszlo Nagy","doi":"10.1172/JCI173858","DOIUrl":"10.1172/JCI173858","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":null,"pages":null},"PeriodicalIF":13.3,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11473166/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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