Clinical and Translational Medicine最新文献

{"title":"The generation of a neuronal phase code for space","authors":"Eran Stark, Hadas E. Sloin","doi":"10.1002/ctm2.70092","DOIUrl":"10.1002/ctm2.70092","url":null,"abstract":"<p>Neurons are thought to represent information by spikes, but which specific aspect of spiking activity represents information is debated. Place coding in the mammalian hippocampus provides a useful system for studying forms of neuronal coding. Individual pyramidal cells in the hippocampal CA1 region spike when an exploring rodent is at a particular part of the environment, the “place field” of the cell.<span><sup>1</sup></span> Place cell firing is a “rate code”, where the rate profile is independent of the millisecond timing of individual spikes.</p><p>During locomotion, local field potentials in the rodent hippocampus exhibit rhythmic theta (4–11 Hz) oscillations. In many place fields, the spikes follow a specific temporal pattern: when the animal enters the field, spikes occur at the peak of the theta wave, and subsequent spikes occur at progressively earlier phases.<span><sup>2</sup></span> Knowing the phase in which a spike occurs can indicate where the animal is within the place field. This “phase precession” is an example of a “phase code”, in which the phase of the individual spike with respect to the ongoing theta may carry information beyond the firing rate.<span><sup>3</sup></span></p><p>The observation that both rate and phase codes may carry information about the same parameter in the same neuron provides an opportunity for understanding how these codes are generated. A priori, there are at least three options (Figure 1): a rate code might be somehow converted into a phase code<span><sup>4</sup></span>; a phase code may be converted into a rate code<span><sup>5</sup></span>; or a third, “progenitor” code could generate both.<span><sup>6</sup></span> Work in the past three decades provided evidence for all three possibilities and for various combinations thereof, and numerous models were proposed for generating phase precession.<span><sup>7</sup></span></p><p>We combined electrophysiological recordings with optogenetic manipulations in freely-moving mice to approach the problem of the generation of rate and phase codes in CA1 pyramidal cells. We reasoned that imposing one code on the system may determine whether the codes are interdependent, and possibly constrain the generative mechanisms. Because multiple prior studies suggested that the phase precession observed in CA1 is inherited from other regions,<span><sup>7</sup></span> we chose to impose a rate code on individual pyramidal cells in CA1.</p><p>The induction of an artificial rate code presents several technical challenges. First, we developed hardware to manipulate the activity of individual neurons deep in the brain of freely-moving subjects.<span><sup>8</sup></span> We invented multi-site/multi-colour optoelectronic devices called “diode-probes” in which light from multiple miniature sources is emitted near the recording electrodes. Second, we coupled the activation of CA1 pyramidal cell spiking with the actual kinematics of the mouse. We developed a system called “Spotter","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11560855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615729","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}

{"title":"Transcriptomic profiling reveals the dynamics of fibrotic progression-related gene expression into post-coronavirus disease 2019 pulmonary fibrosis","authors":"Sabrina Setembre Batah, Andrea Jazel Rodriguez-Herrera, Maria Júlia Faci do Marco, Juliana Rocha Souza Chiappetto, Mariana Gatto, Simone Alves do Vale, Robson Aparecido Prudente, Amanda Piveta Schnepper, Robson Francisco Carvalho, João Paulo Facio Almeida, Tales Rubens de Nadai, Marcel Konigkam Santos, Li Siyuan Wada, José Baddini-Martinez, Danilo Tadao Wada, Andrea Antunes Cetlin, Vera Luiza Capelozzi, Bruno Guedes Baldi, Suzana Tanni, Rosane Duarte Achcar, Alexandre Todorovic Fabro","doi":"10.1002/ctm2.70088","DOIUrl":"10.1002/ctm2.70088","url":null,"abstract":"<p>Dear Editor,</p><p>Our study has identified a gene expression profile associated with the progression of coronavirus disease 2019 (COVID-19) to pulmonary fibrosis in a pro-fibrotic environment similar to that found in fibrosing interstitial lung diseases (f-ILDs). Briefly, we noted the common expression of 86 genes in post-COVID-19 pulmonary fibrosis (post-CPF) and f-ILDs, indicating their likely involvement in perpetuating pulmonary fibrosis through shared fibrotic pathways—confirmed by the in-situ expression of MUC5ac and WNT10a. Furthermore, an additional set of 31 genes exhibited common expression patterns between subacute COVID-19, the so-called organizing diffuse alveolar damage (ODAD), and CPF, as well as f-ILDs. Among those genes, MUC4 and KRT5 were confirmed by immunohistochemistry, suggesting their role as potential predictors for the early outcome of possible pulmonary fibrosis.</p><p>Post-CPF is a long-term complication diagnosed by clinical setting, pulmonary function tests and/or image examinations.<span><sup>1</sup></span> Initially, some COVID-19-infected patients develop acute respiratory distress syndrome (ARDS) during the exudative phase of DAD, marked by cytokine storm and immune cell recruitment.<span><sup>2</sup></span> Following the inflammatory peak and pneumocyte injury, myofibroblast activation triggers extracellular matrix (ECM) deposition, leading to ODAD-phase which typically restores to typical lung architecture. However, some patients progress to pulmonary fibrosis<span><sup>3</sup></span> with morphological changes that are driven by a complex pathophysiological sequence and dynamic gene expression shifts. In the end, the fibrotic outcome can resemble other f-ILDs. Identifying gene expression levels linked to the progression from ODAD to CPF is crucial for finding biomarkers for early diagnosis. Our study aimed to identify potential biomarkers in gene expression associated with fibrotic progression to CPF by analyzing the transcriptome of patients with ODAD, CPF, f-ILDs and controls.</p><p>As previously described by Batah et al.,<span><sup>4</sup></span> autopsies from the ODAD group revealed ODAD-phase with bronchiolar metaplasia, myxoid fibrosis, myofibroblastic activation and extensive alveolar septal thickening with collagen types I and III deposition (Table S1; Figure 1A–C). Meanwhile, after an average of 324.6 days following the initial positive nasopharyngeal swab for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), patients from the CPF group developed pulmonary fibrosis with bronchiolar metaplasia and parenchymal remodelling with increased collagen deposition, especially type I (suppinfo1; Figure 1D–F). Although the common remodelling profile, the differential gene expression (DGE) analysis between ODAD and CPF revealed distinct gene signatures (Figure S1A,B), Some of the top 20 DGEs reflect the manifestation of ARDS in ODAD patients (Figure S1C,D and Table S2). For example, the upregulatio","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11560857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615734","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}

{"title":"Molecular characterization of human HSPCs with different cell fates in vivo using single-cell transcriptome analysis and lentiviral barcoding technology","authors":"Junnan Hua, Ke Wang, Yue Chen, Xiaojing Xu, Guoyi Dong, Yue Li, Rui Liu, Yecheng Xiong, Jiabin Ding, Tingting Zhang, Xinru Zeng, Yuxi Li, Haixi Sun, Ying Gu, Sixi Liu, Wenjie Ouyang, Chao Liu","doi":"10.1002/ctm2.70085","DOIUrl":"10.1002/ctm2.70085","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Hematopoietic stem and progenitor cells (HSPCs) possess the potential to produce all types of blood cells throughout their lives. It is well recognized that HSPCs are heterogeneous, which is of great significance for their clinical applications and the treatment of diseases associated with HSPCs. This study presents a novel technology called Single-Cell transcriptome Analysis and Lentiviral Barcoding (SCALeBa) to investigate the molecular mechanisms underlying the heterogeneity of human HSPCs in vivo. The SCALeBa incorporates a transcribed barcoding library and algorithm to analyze the individual cell fates and their gene expression profiles simultaneously. Our findings using SCALeBa reveal that HSPCs subset with stronger stemness highly expressed <i>MYL6B</i>, <i>ATP2A2</i>, <i>MYO19</i>, <i>MDN1</i>, <i>ING3</i>, and so on. The high expression of <i>COA3</i>, <i>RIF1</i>, <i>RAB14</i>, and <i>GOLGA4</i> may contribute to the pluripotent-lineage differentiation of HSPCs. Moreover, the roles of the representative genes revealed in this study regarding the stemness of HPSCs were confirmed with biological experiments. HSPCs expressing <i>MRPL23</i> and <i>RBM4</i> genes may contribute to differentiation bias into myeloid and lymphoid lineage, respectively. In addition, transcription factor (TF) characteristics of lymphoid and myeloid differentiation bias HSPCs subsets were identified and linked to previously identified genes. Furthermore, the stemness, pluripotency, and differentiation-bias genes identified with SCALeBa were verified in another independent HSPCs dataset. Finally, this study proposes using the SCALeBa-generated tracking trajectory to improve the accuracy of pseudo-time analysis results. In summary, our study provides valuable insights for understanding the heterogeneity of human HSPCs in vivo and introduces a novel technology, SCALeBa, which holds promise for broader applications.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>SCALeBa and its algorithm are developed to study the molecular mechanism underlying human HSPCs identity and function.</li>\u0000 \u0000 <li>The human HSPCs expressing <i>MYL6B, MYO19, ATP2A2, MDN1, ING3</i>, and <i>PHF20</i> may have the capability for high stemness.</li>\u0000 \u0000 <li>The human HSPCs expressing <i>COA3, RIF1, RAB14</i>, and <i>GOLGA4</i> may have the capability for pluripotent-lineage differentiation.</li>\u0000 \u0000 <li>The human HSPCs expressing <i>MRPL23</i> and <i>RBM4</i> genes may have the capability to differentiate into myeloid and lymphoid lineage respectively in vivo.</li>\u0000 \u0000 <li>The legit","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11560861/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615599","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}

{"title":"CLINICAL AND TRANSLATIONAL MEDICINE","authors":"","doi":"10.1002/ctm2.70083","DOIUrl":"https://doi.org/10.1002/ctm2.70083","url":null,"abstract":"","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70083","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142641985","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}

{"title":"Targeting endoplasmic reticulum stress-induced lymphatic dysfunction for mitigating bisphosphonate-related osteonecrosis","authors":"Ziyue Qin, Hanyu Xie, Pengcheng Su, Zesheng Song, Rongyao Xu, Songsong Guo, Yu Fu, Ping Zhang, Hongbing Jiang","doi":"10.1002/ctm2.70082","DOIUrl":"10.1002/ctm2.70082","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Bisphosphonates (BPs) are the first-line treatment to stop bone resorption in diseases, including osteoporosis, Paget's disease, multiple myeloma and bone metastases of cancer. However, BPs-related osteonecrosis of the jaw (BRONJ), characterized by local inflammation and jawbone necrosis, is a severe intractable complication. The cumulative inflammatory burden often accompanies impaired lymphatic drainage, but its specific impact on BRONJ and the underlying mechanisms remain unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The mouse BRONJ model was established to assess the integrity and drainage function of lymphatic vessels by tissue clearing techniques, injected indocyanine green lymphatic clearance assay, flow cytometry analysis and histopathological staining. RNA sequencing, metabolome analysis, transmission electron microscopy and Western blotting were utilized to analyze the impacts of Zoledronate acid (ZA) on endoplasmic reticulum stress (ERS) and function of lymphatic endothelial cells (LECs). By constructing <i>Lyve1<sup>creERT</sup>; SIRT6<sup>f/f</sup></i> and <i>Lyve1<sup>creERT</sup>; ATG5<sup>f/f</sup></i> mice, we evaluated the role of ERS-induced LECs apoptosis in the progression of BRONJ. Additionally, we developed a nanoparticle-loaded ZA and rapamycin (ZDPR) to enhance autophagy and evaluated its potential in mitigating BRONJ.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The mouse BRONJ model displayed impaired lymphatic drainage, accompanied by significant local inflammation and bone necrosis. The prolonged stimulation of ZA resulted in the extension of ERS and the inhibition of autophagy in LECs, ultimately leading to apoptosis. Mechanistically, ZA activated XBP1s through the NAD<sup>+</sup>/SIRT6 pathway, initiating ERS-induced apoptosis in LECs. The conditional knockout mouse models demonstrated that the deletion of <i>SIRT6</i> or <i>ATG5</i> significantly worsened lymphatic drainage and inflammatory infiltration in BRONJ. Additionally, the innovative nanoparticle ZDPR alleviated ERS-apoptosis in LECs and enhanced lymphatic function, facilitating inflammation resolution.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our study has elucidated the role of the NAD<sup>+</sup>/SIRT6/XBP1s pathway in ERS-induced apoptosis in ZA-treated LECs, and further confirmed the therapeutic potential of ZDPR in restoring endothelial function and improving lymphatic drainage, thereby effectively mitigating BRONJ.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11550091/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615636","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}

{"title":"Unsupervised learning-derived phenotypes for personalized fluid management in critically ill patients with heart failure: A multicenter study","authors":"Chengjian Guan, Angwei Gong, Yan Zhao, Hangtian Yu, Shuaidan Zhang, Zhiyi Xie, Yehui Jin, Xiuchun Yang, Jingchao Lu, Bing Xiao","doi":"10.1002/ctm2.70081","DOIUrl":"10.1002/ctm2.70081","url":null,"abstract":"<p>Dear Editor,</p><p>Fluid balance management in critically ill heart failure (HF) patients remains a formidable clinical challenge. While clinicians typically aim for net negative fluid balance to alleviate symptoms, recent studies employing fixed strategies have yielded inconsistent results.<span><sup>1, 2</sup></span> The 2024 Heart Failure Association guidelines of the European Society of Cardiology emphasized the importance of individualized fluid balance strategies, particularly for critically ill patients.<span><sup>3</sup></span> Our study introduces a novel approach using unsupervised learning to identify four distinct phenotypes of critically ill HF patients, each with unique clinical characteristics and fluid balance requirements. To facilitate clinical application, we have developed a user-friendly interface that enables rapid phenotype identification and customized fluid management.</p><p>We utilized two non-overlapping databases: III-CareVue subset and IV versions of the Intensive Care Medical Information Marketplace (MIMIC)<span><sup>4</sup></span> for training cohorts and the eICU Collaborative Research Database (eICU)<span><sup>5</sup></span> for external validation (Method S1). The MIMIC cohort comprised 5998 patients, while the eICU cohort included 2549 patients (Figure S1). We initially extracted 56 variables from the first day of ICU admission. After eliminating variables with more than 30% missing data, 47 variables remained, encompassing demographics, comorbidities, laboratory values, vital signs, interventions, and severity scores. To ensure a balanced contribution of characteristics, all data underwent cleaning and normalization (Method S2, Figure S2). In-hospital mortality served as our primary outcome, with ICU length of stay and total hospital length of stay as secondary outcomes.</p><p>Uniform Manifold Approximation and Projection (UMAP) was used to determine that there were no differences in clinical characteristics between the two training databases (Figure S3). To classify patients, we applied the K-prototypes clustering algorithm, which effectively accommodates mixed numerical and categorical attributes while preserving the characteristics of factorial variables (Method S3). The optimal number of clusters was determined using standard tests, considering both statistical metrics and clinical relevance. This approach ultimately identified four distinct phenotypes (Figure S4).</p><p>Comparative analysis of these phenotypes revealed distinct clinical profiles (Figure 1, Table 1, Table S1). Phenotype A was characterized by aggressive interventions and inflammation, including high rates of vasoactive drug use, antibiotic use, and mechanical ventilation. This group also exhibited the highest white blood cell count and chloride levels, coupled with the lowest platelet count. Phenotype B represented the mildest form with the most favourable prognosis. Phenotype C was distinguished by the highest mean age, lowest body weig","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11546239/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603252","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}

{"title":"Genetic variants explain ancestry-related differences in type 2 diabetes risk","authors":"Aaron J. Deutsch, Kirk Smith, Miriam S. Udler","doi":"10.1002/ctm2.70076","DOIUrl":"10.1002/ctm2.70076","url":null,"abstract":"<p>Type 2 diabetes (T2D) is a global epidemic, affecting over 400 million people around the world.<span><sup>1</sup></span> T2D causes devasting complications and is a leading risk factor for ischaemic heart disease and stroke, which are among the top causes of global morbidity and mortality.<span><sup>1</sup></span> Classically, T2D occurs in adulthood in the setting of obesity and insulin resistance. Increasingly, however, T2D is understood to arise from a complex interplay of environmental and genetic factors, leading to heterogeneity in patient clinical presentation and disease course.<span><sup>2, 3</sup></span> There have been many attempts to define T2D subtypes using a range of analytic methods, but few efforts have shown real-world clinical utility or given insight into disease pathophysiology.<span><sup>4</sup></span></p><p>Over recent years, advances in large-scale genome-wide association studies (GWASs) have uncovered hundreds of genetic variants that modulate T2D risk. This genetic information has the potential to provide insight into disease biology; yet, clinical translation has been limited, often because the strongest genetic associations are not found in protein-coding regions, which makes it more challenging to identify causal genes and pathways. By leveraging the power of GWAS, our laboratory has developed a complex, high-throughput approach to define T2D disease mechanisms, which may help to identify T2D patient subtypes<span><sup>5, 6</sup></span> (Figure 1). This approach aggregates GWAS results to assess the link between genetic variants and diabetes-related clinical traits, such as glucose, haemoglobin A1c and body mass index (BMI). We then apply a machine learning method called Bayesian non-negative matrix factorisation to group together closely related variants and traits into clusters. By analysing the top-weighted variants and traits in each cluster, we can infer the most likely biological mechanism contributing to that cluster. Notably, this ‘soft’ clustering method allows a given variant or trait to be assigned to more than one cluster.</p><p>Most prior genetic analyses have focused on European populations, potentially limiting the applicability for other ancestry groups. To address this limitation, we recently applied our high-throughput pipeline to investigate T2D clusters using current large, multi-ancestry genetic studies.<span><sup>7</sup></span> Through this approach, we confirmed our previously identified T2D genetic clusters and found three new clusters, yielding a total of 12 clusters. Three clusters were associated with beta cell dysfunction and insulin deficiency, while seven were associated with insulin resistance. Among the insulin resistance clusters, certain clusters were associated with obesity and above-average BMI, whereas two other clusters were associated with a ‘lipodystrophy-like’<span><sup>8</sup></span> abnormal fat distribution and below-average BMI. Furthermore, we demonstrated significant ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11537768/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582078","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}

{"title":"Induced collagen type-I secretion by hepatocytes of the melanoma liver metastasis is associated with a reduction in tumour-infiltrating lymphocytes","authors":"Shodai Mizuno, Matias A. Bustos, Yoshinori Hayashi, Kodai Abe, Satoru Furuhashi, Yalda Naeini, Xiaowei Xu, Anton J Bilchik, Dave S. B. Hoon","doi":"10.1002/ctm2.70067","DOIUrl":"10.1002/ctm2.70067","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Overall patients with melanoma liver metastasis (MLiM) have a dismal prognosis and poor responses to the standard of care treatment. Understanding the role of the tumour microenvironment (TME) is critical for discovering better strategies to overcome intrinsic therapy resistance in MLiM. The aim was to understand the crosstalk signalling pathways between hepatocytes and metastatic melanoma cells in the TME of MLiM.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Hepatocytes and melanoma tumour cells of MLiM were assessed using transcriptomic NanoString GeoMx digital spatial profiling (NGDSP) assay. Functional assays were performed using normal hepatocytes and MLiM-derived cell lines. Validation was performed using multiplex immunofluorescence.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In NGDSP analysis adjacent normal hepatocytes (ANH) had higher CXCR4 and COL1A1/2 levels than distant normal hepatocytes (DNH), while melanoma cells had higher TNF-α levels. In vitro, MLiM cell lines released TNF-α which upregulated CXCR4 and CXCL12 levels in ANH. CXCL12 activated CXCR4, which triggered AKT and NFκB signalling pathways. Consequently, AKT signalling induced the upregulation of collagen type I. MLiM were significantly encircled by a shield of collagen, whereas other liver metastases showed reduced levels of collagen. Of all the liver metastasis analyzed, the presence of collagen in melanoma liver metastasis was associated with a reduction in tumour-infiltrating lymphocytes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>MLiM modified ANH to increase collagen production and created a physical barrier. The collagen barrier was associated with a reduction of immune cell infiltration which could potentially deter MLiM immune surveillance and treatment responses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Spatial analyses of melanoma liver metastasis show that adjacent normal hepatocytes have increased collagen-type I levels.</li>\u0000 \u0000 <li>Melanoma liver metastases tumour cells secrete enhanced levels of TNF-α to stimulate CXCR4/CXCL12 upregulation in adjacent normal hepatocytes.</li>\u0000 \u0000 <li>Activation of CXCR4 promotes AKT and NF-κB signalling pathways to promote collagen-type I secretion in adjacent normal hepatocytes.</li>\u0000 \u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70067","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142575382","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}

{"title":"Neutrophil pyroptosis regulates corneal wound healing and post-injury neovascularisation","authors":"Peng Chen,&nbsp;Zhentao Zhang,&nbsp;Lilian Sakai,&nbsp;Yanping Xu,&nbsp;Shanzhi Wang,&nbsp;Kyung Eun Lee,&nbsp;Bingchuan Geng,&nbsp;Jongsoo Kim,&nbsp;Bao Zhao,&nbsp;Qiang Wang,&nbsp;Haitao Wen,&nbsp;Heather L. Chandler,&nbsp;Hua Zhu","doi":"10.1002/ctm2.1762","DOIUrl":"10.1002/ctm2.1762","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Rationale</h3>\u0000 \u0000 <p>The cornea is a unique structure that maintains its clarity by remaining avascular. Corneal injuries can lead to neovascularisation (CNV) and fibrosis and are the third most common cause of blindness worldwide.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Corneal injuries induce an immune cell infiltration to initiate reparative processes. However, inflammation caused by sustained immune cell infiltration is known to be detrimental and can delay the healing process. This study was designed to understand the potential role of neutrophil and epithelial cell crosstalk in post-injury CNV.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods and results</h3>\u0000 \u0000 <p>Western blotting and immunostaining assays demonstrated that neutrophils infiltrated corneas and underwent pyroptosis following acute alkali injury. In vivo studies showed that genetic ablation of Gasdermin D (GsdmD), a key effector of pyroptosis, enhanced corneal re-epithelialisation and suppressed post-injury CNV. In vitro co-culture experiments revealed that interleukin-1β (IL-1β) was released from pyroptotic neutrophils which suppressed migration of murine corneal epithelial cells. Real-time RT-PCR and immunostaining assays identified two factors, Wnt5a and soluble fms-like tyrosine kinase-1 (sflt-1), highly expressed in newly healed epithelial cells. sflt-1 is known to promote corneal avascularity. Bone marrow transplantation, antibody mediated neutrophil depletion, and pharmacological inhibition of pyroptosis promoted corneal wound healing and inhibited CNV in an in vivo murine corneal injury model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Taken together, our study reveals the importance of neutrophil/epithelium crosstalk and neutrophil pyroptosis in response to corneal injuries. Inhibition of neutrophil pyroptosis may serve as a potential treatment to promote corneal healing without CNV.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Neutrophil pyroptosis delays re-epithelialization after corneal injury</li>\u0000 \u0000 <li>Compromised re-epithelialization promotes corneal neovascularization after injury</li>\u0000 \u0000 <li>Inhibition of post-injury pyroptosis could be an effective therapy to promote corneal wound healing.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.1762","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142575384","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}

{"title":"Therapeutic potential of mesenchymal stem cell-derived extracellular vesicles: A focus on inflammatory bowel disease","authors":"Laura Clua-Ferré,&nbsp;Roger Suau,&nbsp;Irene Vañó-Segarra,&nbsp;Iris Ginés,&nbsp;Carolina Serena,&nbsp;Josep Manyé","doi":"10.1002/ctm2.70075","DOIUrl":"10.1002/ctm2.70075","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as key regulators of intercellular communication, orchestrating essential biological processes by delivering bioactive cargoes to target cells. Available evidence suggests that MSC-EVs can mimic the functions of their parental cells, exhibiting immunomodulatory, pro-regenerative, anti-apoptotic, and antifibrotic properties. Consequently, MSC-EVs represent a cell-free therapeutic option for patients with inflammatory bowel disease (IBD), overcoming the limitations associated with cell replacement therapy, including their non-immunogenic nature, lower risk of tumourigenicity, cargo specificity and ease of manipulation and storage.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Main Topics Covered&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;This review aims to provide a comprehensive examination of the therapeutic efficacy of MSC-EVs in IBD, with a focus on their mechanisms of action and potential impact on treatment outcomes. We examine the advantages of MSC-EVs over traditional therapies, discuss methods for their isolation and characterisation, and present mechanistic insights into their therapeutic effects through transcriptomic, proteomic and lipidomic analyses of MSC-EV cargoes. We also discuss available preclinical studies demonstrating that MSC-EVs reduce inflammation, promote tissue repair and restore intestinal homeostasis in IBD models, and compare these findings with those of clinical trials.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Finally, we highlight the potential of MSC-EVs as a novel therapy for IBD and identify challenges and opportunities associated with their translation into clinical practice.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;The source of mesenchymal stem cells (MSCs) strongly influences the composition and function of MSC-derived extracellular vesicles (EVs), affecting their therapeutic potential. Adipose-derived MSC-EVs, known for their immunoregulatory properties and ease of isolation, show promise as a treatment for inflammatory bowel disease (IBD).&lt;/li&gt;\u0000 \u0000 &lt;li&gt;MicroRNAs are consistently present in MSC-EVs across cell types and are involved in pathways that are dysregulated in IBD, making them potential therapeutic agents. For example, miR-let-7a is associated with inhibition of apoptosis, miR-100 supports cell survival, miR-125b helps suppress pro-inflammatory cytokines and miR-20 promotes anti-inflammatory M2 macrophage polar","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70075","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142563856","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}