Clinical and translational discovery最新文献

{"title":"EccDNA, STING activation, and their potential roles in DLBCL prognosis and therapy","authors":"Xi-Bo Hu, Wei-Ying Wang, Xiao-Jian Sun, Qun-Ling Zhang","doi":"10.1002/ctd2.70013","DOIUrl":"https://doi.org/10.1002/ctd2.70013","url":null,"abstract":"<p>Diffuse large B-cell lymphoma (DLBCL), the most common lymphoma in adults, poses a significant clinical challenge due to its marked heterogeneity and high incidence of patients suffering relapse or becoming refractory after the first-line immunochemotherapy. DLBCL cells may originate from different stages of lymphoid differentiation, and thus their gene expression profiling can delineate two distinct molecular subtypes of DLBCL: germinal center B-cell-like (GCB) and activated B-cell-like (ABC) subtypes, with a minority of cases remaining unclassifiable. Alternatively, immunohistochemistry-based algorithms can also dichotomize DLBCL into GCB and non-GCB subtypes. In addition to these classifications related to cell-of-origin, recent in-depth genomic analyses have also revealed recurrent genomic aberrations, prompting the proposal of new classification systems for DLBCL.<span><sup>1, 2</sup></span> However, as yet the correlation between prognosis and molecular subtypes remains elusive.<span><sup>3</sup></span> As an effort to further explore the heterogeneity of DLBCL, in an article recently published in <i>Clinical and Translational Medicine</i>, Wu et al. reported the first profiling of extrachromosomal circular DNA (eccDNA) in DLBCL cells and identified the oncogenic role and prognostic significance of the eccDNAs in DLBCL. Meanwhile, their multi-omic and mechanistic studies uncovered an activation of the stimulator of interferon genes (STING) signalling pathway by eccDNAs in DLBCL cells, thus suggesting a potential therapeutic approach combining chemotherapy with STING inhibition (Figure 1).<span><sup>4</sup></span></p><p>EccDNAs are circular double-strand DNA molecules that are originally derived from, but physically independent of, chromosomal DNA. They are heterogeneous in size ranging from a few hundred to millions of base pairs and appear to be derived from either repetitive sequences or unique genomic sequences, and many eccDNAs can be self-replicated. While the biogenesis and functions of eccDNAs remain to be fully understood, an increase in eccDNA has been observed in several types of human cancers. Importantly, because the eccDNAs provide a significant source of oncogene amplification and can be segregated unequally to daughter cells, they are believed to contribute enormously to tumour evolution and intratumor heterogeneity,<span><sup>5</sup></span> and the presence of eccDNAs in patient tumour samples has been found to be associated with poor outcomes across many types of cancers.<span><sup>6</sup></span> Furthermore, studies have shown that eccDNAs can function as potent innate immunostimulants, which require the STING signalling pathways to serve as intracellular DNA sensors.<span><sup>7</sup></span></p><p>By integrating circular DNA sequencing (circle-seq), atomic force microscopy, whole exome sequencing (WES) and single-cell RNA sequencing (scRNA-seq) techniques, Wu et al. performed a comprehensive eccDNA profiling of 18 DLBC","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"4 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70013","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142524934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating single-cell RNA sequencing data to decipher heterogeneity and function of macrophages in various organs and diseases","authors":"Xinjie Xu, Zichen Wu, Zhiwei Zeng, Jiaying Cao, Liang Chen","doi":"10.1002/ctd2.70005","DOIUrl":"https://doi.org/10.1002/ctd2.70005","url":null,"abstract":"<p>Macrophages are essential components of the innate immune system, playing crucial roles in host defence, immune surveillance and tissue repair processes. Developmentally, macrophages can be divided into embryonic origin and postnatal origin.<span><sup>1</sup></span> Embryonic-origin macrophages are derived from the yolk sac and foetal liver during embryogenesis. They migrate to tissues early in development and maintain their populations with self-renewal mechanisms throughout the lifecycle. These macrophages are commonly found in tissues such as the brain (microglia), liver (Kupffer cells) and lungs (alveolar macrophages). In contrast, postnatal-origin macrophages are derived from hematopoietic stem cells in the bone marrow. During instances of injury, inflammation or tumorigenesis, monocytes are mobilized from the bone marrow to the blood and differentiate into macrophages upon reaching distinct tissues. Functionally, macrophages have traditionally been classified into M1 and M2 types based on in vitro activation modes. M1 macrophages exhibit pro-inflammatory properties, while M2 macrophages are involved in anti-inflammatory responses and tissue repair. M2 macrophages are further classified into subtypes M2a, M2b, M2c and M2d based on distinct activation signals.<span><sup>2</sup></span> However, recent perspectives suggest that macrophage functions exist on a spectrum rather than binary states, with significant heterogeneity across organs and diseases, challenging the simplistic polarization classification in explaining diverse pathophysiological processes.</p><p>The advent of single-cell RNA sequencing (scRNA-seq) technology has revolutionized the study of macrophages, providing unprecedented resolution to unravel their origin, heterogeneity and functional diversity in various physiological and pathological contexts. The integrated multi-organ scRNA-seq studies of macrophages aim to address the following key scientific questions: 1. Deciphering macrophage heterogeneity: Several studies integrated macrophages from normal tissues and tumour tissues of different organs for fine annotation, revealing significant heterogeneity of macrophages, rather than polarized classification.<span><sup>3, 4</sup></span> 2. Functional regulation of macrophage: In-depth analysis of macrophage function is crucial, such as inflammatory response and metabolism, thus informing therapeutic strategies aimed at modulating macrophage activity. For instance, TREM2+ macrophages have been identified in the brain, fat, liver, blood vessels and other physiological and pathological conditions, and have diverse functions such as phagocytosis, metabolism and pro-inflammatory effects.<span><sup>5</sup></span> SPP1+ macrophages have been identified in different diseases such as tumours and atrial fibrillation, and have diverse functions such as promoting fibrosis and regulating immunity.<span><sup>6</sup></span> 3. Inference of macrophage lineage origin and differentiation traj","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"4 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142524932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"“Single-cell multimodal chromatin profiles revealing epigenetic regulations of cells in hepatocellular carcinoma”","authors":"Vikas Kumar,&nbsp;Samuel Beck","doi":"10.1002/ctd2.70002","DOIUrl":"https://doi.org/10.1002/ctd2.70002","url":null,"abstract":"<p>Hepatocellular carcinoma (HCC), with its increasing prevalence globally, is emerging as a major health challenge. Hepatocellular carcinoma cells exhibit both significant homogeneity and heterogeneity, governed by complex epigenomic regulations. Recently, numerous single-cell unimodal techniques have been used to study HCC at various levelswhich have already revealed a complex interplay at genomic, transcriptomic, spatial and epigenomic levels. However, the use of single-cell multimodal techniques combining different unimodal layers in HCC remains quite limited, necessitating further studies focusing on these methods to uncover novel markers, and mechanisms at epigenetic levels. In this commentary, we highlight how integrating multimodal approaches with epigenetic modifications can provide new insights into HCC and foster future therapeutic advancements.</p>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"4 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liquid biopsy—A biomarker-based revolutionising technique in cancer therapy","authors":"Subham Sarkar,&nbsp;Samraggi Chakraborty,&nbsp;Soubhagya Ghosh,&nbsp;Ekanansha Roy Chowdhury,&nbsp;Jenifer Rajak,&nbsp;Arup Kumar Mitra,&nbsp;Ajoy Kumer,&nbsp;Bikram Dhara","doi":"10.1002/ctd2.70006","DOIUrl":"https://doi.org/10.1002/ctd2.70006","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Cancer has grabbed the attention of scientists and medical professionals all over the world much more than any other disease. In the past few decades, the medical field has improved quite a lot but progress in the path to find a solution for cancer is very less. As the popularity of invasive technologies is diminishing in cancer treatment, scientists have come up withminimally invasive or non-invasive alternatives, among which liquid biopsy, by far is the most suitable.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Liquid biopsy is used to analyse nucleic acids, subcellular components and circulating tumour cells in various biological fluids for diagnosis of cancer. It can also be used to know the efficacy of cancer drugs in a patient by analysing multiple samples.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Outcomes</h3>\u0000 \u0000 <p>Liquid biopsy is becoming standard of care as it allows biopsy of those samples in which solid tumour biopsies are not possible. The diversity of sampling procedures, such as collection of urine for urothelial carcinoma or bladder or prostate cancer and phlebotomy for other types of cancer, make liquid biopsy one of the best methods for diagnosis of cancer.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This review aims in discussing the several techniques used for the detection of cancer biomarkers and some clinical manifestations due to the changes in the biomarkers which are analysed by liquid biopsy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"4 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142404561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Developing messenger RNA biomarkers: A workflow to characterise and identify transcript target sequences unaffected by alternative splicing for reproducible gene transcript quantification by reverse transcriptase quantitative polymerase chain reaction","authors":"Bhaja Krushna Padhi,&nbsp;Guillaume Pelletier","doi":"10.1002/ctd2.70009","DOIUrl":"https://doi.org/10.1002/ctd2.70009","url":null,"abstract":"<p>Most eukaryotic genes generate multiple messenger RNA (mRNA) transcript variants by alternative splicing. The incomplete annotation of gene transcripts in genomic databases can result in improper primer design, adversely affecting the reliability of gene expression measurements by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). Hence, we present a workflow combining bioinformatics analyses, to select two to three evolutionarily conserved constitutive exons in rats, mice and humans as target sequences for PCR primer design, with experimental RT-PCR amplification and amplicon sequencing to confirm the expression and identity of gene transcript targets. The application of this workflow to the characterization of neurodevelopmental biomarker genes identified an unannotated exon in the rat Map2 gene, illustrating the importance of target sequence validation for the development of translational mRNA biomarkers for toxicological and biomedical studies.</p>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"4 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70009","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142404298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endothelial cell senescence contributes to pathological retinal angiogenesis","authors":"Zehui Shi,&nbsp;Bo Liu,&nbsp;Jinhui Dai,&nbsp;Xiuping Chen","doi":"10.1002/ctd2.70007","DOIUrl":"https://doi.org/10.1002/ctd2.70007","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Pathological retinal neovascularization is marked by microvascular lesions manifested initially as endothelial cell dysfunction and metabolic disturbances. However, the regulatory mechanism guiding retinal vascular endothelial cell function remian controversial.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Main body</h3>\u0000 \u0000 <p>Previous studies have demonstarted that high glucose or oxidative stress can induce premature senescence in endothelial cells, triggering inflammatory responses within the vascular system and promoting the secretion of pro-inflammatory factors, ultimately leading to pathological angiogenesis. Endothelial cell senescence has thus become a key target for anti-angiogenic therapies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This review delves into current research on the mechanisms driving senescence-induced retinal angiogenesis and highlights potential target protein pathways, aiming to provide insights for future investigations.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"4 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70007","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142404185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inflammatory-associated myeloid dendritic cells reveals associations between chronic lung diseases and lung cancer","authors":"Zhiyu Chen,&nbsp;Jiawei Zou,&nbsp;Fulan Deng,&nbsp;Yaoqing Chu,&nbsp;Lianjiang Tan,&nbsp;Xin Zou,&nbsp;Jie Hao","doi":"10.1002/ctd2.70003","DOIUrl":"https://doi.org/10.1002/ctd2.70003","url":null,"abstract":"<p>The high risk of patients with chronic lung diseases in developing into lung cancer has been recognised, but the key factors driving such procedure are still barely known. Dendritic cells (DCs) as major antigen presenting cells take part in the immune response in the very upstream, and myeloid DCs regulate the inflammation in pulmonary diseases. In this article, we performed single-cell RNA sequencing (scRNA-seq) analyses on DCs from pulmonary diseases. We explore the DC characteristics in chronic lung diseases, lung cancer and healthy control samples. We discover that a special type of DC, which is highly associated with inflammatory, inf-DC, is abundant in lung cancer samples. Furthermore, we find that there are about 10% patients with chronic lung diseases also has such inf-DC-rich pattern. Such proportion is consistent to the fact that about 10% chronic lung disease patients finally developed into cancer. Our findings indicate inf-DC could be a potential factor to predict the risk of chronic lung disease developing into cancer.</p>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"4 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.70003","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142404218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic regulation of Epstein–Barr virus: From bench to bedside","authors":"Xiao Gao,&nbsp;Hao-Xu Yang,&nbsp;Shu Cheng,&nbsp;Hua-Man Cai,&nbsp;Jie Xiong,&nbsp;Wei-Li Zhao","doi":"10.1002/ctd2.357","DOIUrl":"https://doi.org/10.1002/ctd2.357","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Epstein–Barr virus (EBV) is a double-stranded DNA herpesvirus and establishes life-long infection in 95% of the world's populations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Main body</h3>\u0000 \u0000 <p>EBV is critically involved in multiple diseases. Aberrant signaling pathways, immune escape, and metabolic reprogramming play essential roles in EBV-mediated pathogenesis. However, the underlying mechanisms have not yet been fully elucidated. Here we reviewed recent advances on the epigenetic regulation of EBV pathogenesis, which may translate to potential therapeutic strategies in EBV-associated diseases.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Growing evidence has suggested that viral infections reconstruct epigenome to modulate gene expression both in the host and the virus levels.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"4 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.357","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142404815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prediction factors and models for chronic kidney disease in type 2 diabetes mellitus: A review of the literature","authors":"Yan Yang,&nbsp;Bixia Yang,&nbsp;Bin Wang,&nbsp;Hua Zhou,&nbsp;Min Yang,&nbsp;Bicheng Liu","doi":"10.1002/ctd2.355","DOIUrl":"https://doi.org/10.1002/ctd2.355","url":null,"abstract":"<p>Diabetes mellitus (DM) has become a major chronic disease seriously affecting human health. Type 2 diabetes mellitus (T2DM) accounts for about 90% of DM patients, which is the largest type. Approximately 25–35% of T2DM patients develop kidney disease, which not only impacts the survival rate and quality of life but also, to the family and society, are of great economic burden. Early identification of high-risk T2DM patients with kidney disease is crucial for initiating targeted prevention and treatment measures in time to reduce or delay the occurrence and progression of diabetic kidney disease. Previous studies have identified a variety of clinical predictors for the progression of renal function in T2DM patients, including proteinuria, estimated glomerular filtration rate, blood glucose, blood pressure, serum uric acid, dyslipidemia, obesity, smoking, duration of DM, age, gender, race, family history of DM, and diabetic retinopathy. Clinical prediction models based on conventional clinical indicators are instrumental in evaluating the risk of kidney disease in T2DM patients, assisting in patient risk stratification. This article systematically reviews the clinical prediction factors and prediction models associated with the progression of renal function in T2DM patients, providing a comprehensive and current reference for improved clinical assessment of the risk of renal function progression.</p>","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"4 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.355","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142152146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell RNA sequencing data identify a conserved population of metallothionein-expressing macrophages that may be ubiquitous in vital human organs","authors":"Joseph A. Daccache,&nbsp;Francis Eng,&nbsp;Lei Cao,&nbsp;Ning Ma,&nbsp;Stephen C. Ward,&nbsp;Thomas Schiano,&nbsp;Mark Miller,&nbsp;Daniel Herron,&nbsp;Anthony V. Azzara,&nbsp;Steven S. Pullen,&nbsp;Paolo Guarnieri,&nbsp;Costica Aloman,&nbsp;Andrea D. Branch","doi":"10.1002/ctd2.348","DOIUrl":"https://doi.org/10.1002/ctd2.348","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;We used publicly available single-cell RNA sequencing data to identify conserved tissue macrophage populations in human organs. Among the subsets, we found a rare population of metallothionein-expressing macrophages that are present in all vital organs analyzed. We deeply phenotype this subset and determine their localization in the human liver.&lt;/p&gt;&lt;p&gt;In the first phase, we collected data from 10 livers,&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; 21 kidneys&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; and 60 lungs,&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; and selected myeloid-lineage cells using published annotations and lineage markers: CD68, S100, HLA-II, LYZ, C1Q, and CD74 (Figure S1). After removing dendritic cells, we subclustered monocytes and macrophages (liver, 8,197; kidney, 5,005; lung, 121,536), and identified eight subclusters in the monocyte-macrophage (mono-mac) space, defined by their differentially expressed genes (DEGs) (Figure 1A and Figure S2). We evaluated the relatedness of subclusters across organs by determining the Pearson correlations of fold-changes of 1126 DEGs that were significant [&lt;i&gt;p&lt;/i&gt;.adj &lt; .05 (Bonferroni)] in at least two organs (Figure 1B). Cross-organ correlations confirmed the relatedness of most subsets and were highest for monocytes and cycling macrophages.&lt;/p&gt;&lt;p&gt;A survey of the mono-mac subtypes present in at least two human organs revealed that the abundances of most were similar across organs, but MAC_RES was disproportionately large in the lung (alveolar macrophages) and absent from the kidney (Figure 1C). Subset abundances were compared between fibrotic and control organs and differed significantly for three: monocytes, MAC_RES and &lt;i&gt;SPP1&lt;/i&gt;&lt;sup&gt;+&lt;/sup&gt; macrophages (Figure S2). While most of the eight subsets are widely known, we found an unexpected, small population of macrophages (∼2.5% of each organ) that highly expressed genes coding for metallothioneins (MAC_MT). Metallothioneins are low molecular weight, cysteine-rich proteins that bind metal ions. They enhance angiogenesis, protect against oxidative stress and metal toxicity, and modulate macrophage function.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Gene expression patterns of MAC_MTs were highly correlated across all three organs. Using a Wilcoxon rank-sum test to calculate DEGs, nine genes were significant [FC &gt; 0, &lt;i&gt;p&lt;/i&gt;.adj &lt; .05 (Bonferroni)] in MAC_MTs in all three organs (Figure 1D). Genes encoding metallothioneins were highly expressed by MAC_MTs only, unlike &lt;i&gt;CTSL&lt;/i&gt; and &lt;i&gt;SGK1&lt;/i&gt;, which were expressed by multiple sub-clusters. Of interest, &lt;i&gt;MTF1&lt;/i&gt; and &lt;i&gt;MTF2&lt;/i&gt;, which encode metallothionein transcription factors, were minimally expressed in MAC_MTs but were highly expressed in the CYCLING subset, which may provide a local source of MAC_MTs.&lt;/p&gt;&lt;p&gt;In each organ, two gene signatures were developed, one distinguished MAC_MTs from other non-dendritic myeloid-lineage cells, and the other distinguished MAC_MTs from all other cells in the organ. To generate ","PeriodicalId":72605,"journal":{"name":"Clinical and translational discovery","volume":"4 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctd2.348","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142099941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}