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Modulation of β-Catenin promotes WNT expression in macrophages and mitigates intestinal injury.
IF 8.2 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2025-02-11 DOI: 10.1186/s12964-025-02065-7
Rishi Man Chugh, Payel Bhanja, Ryan Zitter, Sumedha Gunewardena, Rajeev Badkul, Subhrajit Saha

Background: Macrophages are the major source of WNT ligands. However, the regulation of WNT expression in macrophages has not been studied. In the present study, we have discovered that activation of canonical β-Catenin signaling suppresses WNT expression in macrophages. EVs from these pre-conditioned macrophages promoted intestinal stem cell regeneration and mitigated intestinal injury.

Method: ChIP-seq analysis and validation studies using recombinant DNA construct expressing Luciferase reporter under WNT promoter (e.g. WNT5a and WNT9b) were conducted to demonstrate the involvement of β-Catenin in the transcriptional regulation of WNT expression. The regulatory role of β-Catenin in WNT expression in macrophages was examined by treating these cells with a Tankyrase inhibitor. In addition, the gene expressing β-Catenin was deleted in macrophages using Csf1r.iCre; Ctnnb1fl/fl mice model. Both pharmacological and genetically modulated macrophages were examined for WNT expression and activity by qPCR and TCF/LEF luciferase assay respectively. Additionally, Csf1r.iCre; Ctnnb1fl/fl mice were exposed to irradiation to compare the radiosensitivity with their wildtype littermate. Extracellular vesicles (EVs) were isolated from pre-conditioned WNT-enriched macrophages and infused in irradiated C57BL/6 and Lgr5/eGFP-IRES-Cre-ERT2; R26-ACTB-tdTomato-EGFP mice to determine the regenerative response of intestinal stem cell (ISC) and epithelial repair. Regenerative effects of EVs were also examined in mice model DSS induced colitis.

Result: ChIP-seq analysis and subsequent validation study suggested physical association of β-Catenin with WNT promoters to suppress WNT expression. Macrophage specific deletion of gene expressing β-Catenin or pharmacological inhibition of Tankyrase improves the WNT expression in macrophages several folds compared to control. Transfusion of these preconditioned macrophages or EVs from these cells delivers optimum level of morphogenic WNT to injured epithelium, activates ISC regeneration and mitigated radiation induced intestinal injury. Intestinal epithelium in Csf1r.iCre; Ctnnb1fl/fl mice also showed radioresistance compared to wild type littermate. Moreover, EVs derived from WNT enriched macrophages can mitigate intestinal injury in mice model of DSS induced acute colitis.

Conclusion: The study provides substantial evidence that macrophage-targeted modulation of canonical WNT signaling induces WNT expression in macrophages. Treatment with preconditioned macrophage derived WNT-enriched EVs can be a promising therapeutic approach against intestinal injury.

{"title":"Modulation of β-Catenin promotes WNT expression in macrophages and mitigates intestinal injury.","authors":"Rishi Man Chugh, Payel Bhanja, Ryan Zitter, Sumedha Gunewardena, Rajeev Badkul, Subhrajit Saha","doi":"10.1186/s12964-025-02065-7","DOIUrl":"10.1186/s12964-025-02065-7","url":null,"abstract":"<p><strong>Background: </strong>Macrophages are the major source of WNT ligands. However, the regulation of WNT expression in macrophages has not been studied. In the present study, we have discovered that activation of canonical β-Catenin signaling suppresses WNT expression in macrophages. EVs from these pre-conditioned macrophages promoted intestinal stem cell regeneration and mitigated intestinal injury.</p><p><strong>Method: </strong>ChIP-seq analysis and validation studies using recombinant DNA construct expressing Luciferase reporter under WNT promoter (e.g. WNT5a and WNT9b) were conducted to demonstrate the involvement of β-Catenin in the transcriptional regulation of WNT expression. The regulatory role of β-Catenin in WNT expression in macrophages was examined by treating these cells with a Tankyrase inhibitor. In addition, the gene expressing β-Catenin was deleted in macrophages using Csf1r.iCre; Ctnnb1<sup>fl/fl</sup> mice model. Both pharmacological and genetically modulated macrophages were examined for WNT expression and activity by qPCR and TCF/LEF luciferase assay respectively. Additionally, Csf1r.iCre; Ctnnb1<sup>fl/fl</sup> mice were exposed to irradiation to compare the radiosensitivity with their wildtype littermate. Extracellular vesicles (EVs) were isolated from pre-conditioned WNT-enriched macrophages and infused in irradiated C57BL/6 and Lgr5/eGFP-IRES-Cre-ERT2; R26-ACTB-tdTomato-EGFP mice to determine the regenerative response of intestinal stem cell (ISC) and epithelial repair. Regenerative effects of EVs were also examined in mice model DSS induced colitis.</p><p><strong>Result: </strong>ChIP-seq analysis and subsequent validation study suggested physical association of β-Catenin with WNT promoters to suppress WNT expression. Macrophage specific deletion of gene expressing β-Catenin or pharmacological inhibition of Tankyrase improves the WNT expression in macrophages several folds compared to control. Transfusion of these preconditioned macrophages or EVs from these cells delivers optimum level of morphogenic WNT to injured epithelium, activates ISC regeneration and mitigated radiation induced intestinal injury. Intestinal epithelium in Csf1r.iCre; Ctnnb1<sup>fl/fl</sup> mice also showed radioresistance compared to wild type littermate. Moreover, EVs derived from WNT enriched macrophages can mitigate intestinal injury in mice model of DSS induced acute colitis.</p><p><strong>Conclusion: </strong>The study provides substantial evidence that macrophage-targeted modulation of canonical WNT signaling induces WNT expression in macrophages. Treatment with preconditioned macrophage derived WNT-enriched EVs can be a promising therapeutic approach against intestinal injury.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"78"},"PeriodicalIF":8.2,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11818365/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143400793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
TGF-β1 Induces Mucosal Mast Cell Genes and is Negatively Regulated by the IL-3/ERK1/2 Axis.
IF 8.2 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2025-02-11 DOI: 10.1186/s12964-025-02048-8
Steffen K Meurer, Gina Bronneberg, Christian Penners, Marlies Kauffmann, Till Braunschweig, Christian Liedtke, Michael Huber, Ralf Weiskirchen

Mast cells develop from the myeloid lineage and are released from the bone marrow as immature cells, which then differentiate at the destination tissue based on cues from the local environment. In the liver, mast cells are recruited in diseased states to fibrogenic surroundings rich in TGF-β1. The aim of this study was to investigate TGF-β1 signaling in primary and permanent mast cells to identify common and unique mechanisms. The TGF-β receptor repertoire is similar among mast cells, with high expression of type I and type II receptors and very low expression of type III receptors (Betaglycan and Endoglin). Downstream, TGF-β1 activates the SMAD2/3 signaling axis and also SMAD1/5 with target genes Smad6 and Id1 in a transient manner. Initially, TGF-β1 upregulates the transcription of mucosal mast cell effectors Mcpt1 and Mcpt2 in all analyzed mast cells. This upregulation is reduced in the presence of IL-3, which promotes proliferation. Inhibition of ERK1/2 activation reduces proliferation and mitigates the negative effect of IL-3 on Mcpt1 mRNA and protein expression in the immortalized mast cell line PMC-306 but not in bone marrow-derived mast cells. Therefore, extracellular signal-regulated kinases ERK1/2 are identified as a mutual switch between IL-3-driven proliferation and TGF-β1-promoted mucosal mast cell differentiation in PMC-306. In conclusion, TGF-β1 promotes a mucosal gene signature and inhibits proliferation in mast cells, with these effects being counter-regulated by IL-3/ERK1/2.

{"title":"TGF-β1 Induces Mucosal Mast Cell Genes and is Negatively Regulated by the IL-3/ERK1/2 Axis.","authors":"Steffen K Meurer, Gina Bronneberg, Christian Penners, Marlies Kauffmann, Till Braunschweig, Christian Liedtke, Michael Huber, Ralf Weiskirchen","doi":"10.1186/s12964-025-02048-8","DOIUrl":"10.1186/s12964-025-02048-8","url":null,"abstract":"<p><p>Mast cells develop from the myeloid lineage and are released from the bone marrow as immature cells, which then differentiate at the destination tissue based on cues from the local environment. In the liver, mast cells are recruited in diseased states to fibrogenic surroundings rich in TGF-β1. The aim of this study was to investigate TGF-β1 signaling in primary and permanent mast cells to identify common and unique mechanisms. The TGF-β receptor repertoire is similar among mast cells, with high expression of type I and type II receptors and very low expression of type III receptors (Betaglycan and Endoglin). Downstream, TGF-β1 activates the SMAD2/3 signaling axis and also SMAD1/5 with target genes Smad6 and Id1 in a transient manner. Initially, TGF-β1 upregulates the transcription of mucosal mast cell effectors Mcpt1 and Mcpt2 in all analyzed mast cells. This upregulation is reduced in the presence of IL-3, which promotes proliferation. Inhibition of ERK1/2 activation reduces proliferation and mitigates the negative effect of IL-3 on Mcpt1 mRNA and protein expression in the immortalized mast cell line PMC-306 but not in bone marrow-derived mast cells. Therefore, extracellular signal-regulated kinases ERK1/2 are identified as a mutual switch between IL-3-driven proliferation and TGF-β1-promoted mucosal mast cell differentiation in PMC-306. In conclusion, TGF-β1 promotes a mucosal gene signature and inhibits proliferation in mast cells, with these effects being counter-regulated by IL-3/ERK1/2.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"76"},"PeriodicalIF":8.2,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11817834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143400804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Molecular landscape of tumor-associated tissue-resident memory T cells in tumor microenvironment of hepatocellular carcinoma.
IF 8.2 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2025-02-11 DOI: 10.1186/s12964-025-02070-w
Mi-So Park, Hyeonbin Jo, Hyeree Kim, Ji Young Kim, Woong-Yang Park, Yong-Han Paik, Yeup Yoon, Wonseok Kang, Hong-Hee Won

Background: Immunotherapy for liver cancer is used to rejuvenate tumor-infiltrating lymphocytes by modulating the immune microenvironment. Thus, early protective functions of T cell subtypes with tissue-specific residency have been studied in the tumor microenvironment (TME). We identified tumor-associated tissue-resident memory T (TA-TRM) cells in hepatocellular carcinoma (HCC) and characterized their molecular signatures.

Methods: We obtained single-cell RNA and single-cell TCR sequencing data from five patients with HCC. The heterogeneous characteristics of TRM cell subsets within the TME were then investigated and validated. Risk scores were calculated for survival analysis using significant core marker genes based on data from The Cancer Genome Atlas and the International Cancer Genome Consortium. The signaling pathways, trajectories, and clonal diversity of TA-TRM cells were investigated.

Results: We characterized two TRM clusters (CD69+ and CD103+) that expressed unique signature genes and validated their similar molecular patterns in an independent dataset. Risk scores based on core gene expression in TA-TRM cells were associated with survival in both datasets. Trajectory analysis revealed that the two lineages followed different trajectory paths with distinct marker gene expression across pseudo-time. CD103+ TA-TRM cells showed diverse clonotypes and shared clonotypes with other cell groups. Lower clonal diversity and distinct signaling interactions were observed in the recurrent than in the non-recurrent samples. The CXCL13-CXCR3 interaction between CD103+ TA-TRM and regulatory T cells was observed only in the recurrent samples.

Conclusions: We identified two subtypes of TA-TRM cells in HCC and demonstrated their unique molecular signatures, relevance to survival, and distinct signaling networks according to recurrence. The study findings provide a better understanding of the molecular characteristics of TA-TRM cells in HCC and potential immunotherapeutic strategies.

{"title":"Molecular landscape of tumor-associated tissue-resident memory T cells in tumor microenvironment of hepatocellular carcinoma.","authors":"Mi-So Park, Hyeonbin Jo, Hyeree Kim, Ji Young Kim, Woong-Yang Park, Yong-Han Paik, Yeup Yoon, Wonseok Kang, Hong-Hee Won","doi":"10.1186/s12964-025-02070-w","DOIUrl":"10.1186/s12964-025-02070-w","url":null,"abstract":"<p><strong>Background: </strong>Immunotherapy for liver cancer is used to rejuvenate tumor-infiltrating lymphocytes by modulating the immune microenvironment. Thus, early protective functions of T cell subtypes with tissue-specific residency have been studied in the tumor microenvironment (TME). We identified tumor-associated tissue-resident memory T (TA-T<sub>RM</sub>) cells in hepatocellular carcinoma (HCC) and characterized their molecular signatures.</p><p><strong>Methods: </strong>We obtained single-cell RNA and single-cell TCR sequencing data from five patients with HCC. The heterogeneous characteristics of T<sub>RM</sub> cell subsets within the TME were then investigated and validated. Risk scores were calculated for survival analysis using significant core marker genes based on data from The Cancer Genome Atlas and the International Cancer Genome Consortium. The signaling pathways, trajectories, and clonal diversity of TA-T<sub>RM</sub> cells were investigated.</p><p><strong>Results: </strong>We characterized two T<sub>RM</sub> clusters (CD69<sup>+</sup> and CD103<sup>+</sup>) that expressed unique signature genes and validated their similar molecular patterns in an independent dataset. Risk scores based on core gene expression in TA-T<sub>RM</sub> cells were associated with survival in both datasets. Trajectory analysis revealed that the two lineages followed different trajectory paths with distinct marker gene expression across pseudo-time. CD103<sup>+</sup> TA-T<sub>RM</sub> cells showed diverse clonotypes and shared clonotypes with other cell groups. Lower clonal diversity and distinct signaling interactions were observed in the recurrent than in the non-recurrent samples. The CXCL13-CXCR3 interaction between CD103<sup>+</sup> TA-T<sub>RM</sub> and regulatory T cells was observed only in the recurrent samples.</p><p><strong>Conclusions: </strong>We identified two subtypes of TA-T<sub>RM</sub> cells in HCC and demonstrated their unique molecular signatures, relevance to survival, and distinct signaling networks according to recurrence. The study findings provide a better understanding of the molecular characteristics of TA-T<sub>RM</sub> cells in HCC and potential immunotherapeutic strategies.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"80"},"PeriodicalIF":8.2,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11818299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143400796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Inhibition of tubular epithelial cells ferroptosis alleviates renal interstitial fibrosis by reducing lipid hydroperoxides and TGF-β/Smad signaling.
IF 8.2 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2025-02-11 DOI: 10.1186/s12964-025-02068-4
Yuting Chen, Yue Dai, Yi Huang, Le Zhang, Cuntai Zhang, Hongyu Gao, Qi Yan

Background: Ferroptosis is a non-apoptotic form of regulated cell death that involves an imbalance in the homeostasis of two elements: iron and lipid hydroperoxides. The accumulation of lipid hydroperoxide serves as a key trigger for initiating ferroptosis. Recent studies have identified ferroptosis as a critical pathophysiology contributing to kidney disease progression. However, the specific mechanisms underlying the role of ferroptosis in chronic kidney disease (CKD) have not been elucidated.

Methods: Tubular epithelial cells (TECs) ferroptosis was evaluated in unilateral ureteral obstruction (UUO) models and in TGF-β-treated HK-2 cells to explore the relationship between ferroptosis and fibrosis. Ferroptosis inhibitors (ferrostatin-1) and TECs-targeted glutathione peroxidase 4 (GPX4) overexpression in vivo and in vitro were used to investigate the effect and mechanism of TECs ferroptosis on fibrosis progression.

Results: Our findings indicate that ferroptosis is persistently activated during various states of the UUO model. As the results, ferroptosis was identified as a core facilitator of renal interstitial fibrosis in TECs during UUO. The reduction in TECs ferroptosis significantly ameliorated renal fibrosis and maintained the structure in the proximal tubules. Persistent activation of TECs ferroptosis effectively aggravated fibrosis progression through the TGF-β/Smad pathway.

Conclusions: Inhibiting ferroptosis effectively rescues the accumulation of profibrotic cytokines, thereby alleviating renal fibrosis. The profibrotic mechanism of ferroptosis is closely related to the TGF-β/Smad pathway, and targeting ferroptosis and increasing GPX4 expression could be an effective strategy for treating CKD.

{"title":"Inhibition of tubular epithelial cells ferroptosis alleviates renal interstitial fibrosis by reducing lipid hydroperoxides and TGF-β/Smad signaling.","authors":"Yuting Chen, Yue Dai, Yi Huang, Le Zhang, Cuntai Zhang, Hongyu Gao, Qi Yan","doi":"10.1186/s12964-025-02068-4","DOIUrl":"10.1186/s12964-025-02068-4","url":null,"abstract":"<p><strong>Background: </strong>Ferroptosis is a non-apoptotic form of regulated cell death that involves an imbalance in the homeostasis of two elements: iron and lipid hydroperoxides. The accumulation of lipid hydroperoxide serves as a key trigger for initiating ferroptosis. Recent studies have identified ferroptosis as a critical pathophysiology contributing to kidney disease progression. However, the specific mechanisms underlying the role of ferroptosis in chronic kidney disease (CKD) have not been elucidated.</p><p><strong>Methods: </strong>Tubular epithelial cells (TECs) ferroptosis was evaluated in unilateral ureteral obstruction (UUO) models and in TGF-β-treated HK-2 cells to explore the relationship between ferroptosis and fibrosis. Ferroptosis inhibitors (ferrostatin-1) and TECs-targeted glutathione peroxidase 4 (GPX4) overexpression in vivo and in vitro were used to investigate the effect and mechanism of TECs ferroptosis on fibrosis progression.</p><p><strong>Results: </strong>Our findings indicate that ferroptosis is persistently activated during various states of the UUO model. As the results, ferroptosis was identified as a core facilitator of renal interstitial fibrosis in TECs during UUO. The reduction in TECs ferroptosis significantly ameliorated renal fibrosis and maintained the structure in the proximal tubules. Persistent activation of TECs ferroptosis effectively aggravated fibrosis progression through the TGF-β/Smad pathway.</p><p><strong>Conclusions: </strong>Inhibiting ferroptosis effectively rescues the accumulation of profibrotic cytokines, thereby alleviating renal fibrosis. The profibrotic mechanism of ferroptosis is closely related to the TGF-β/Smad pathway, and targeting ferroptosis and increasing GPX4 expression could be an effective strategy for treating CKD.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"81"},"PeriodicalIF":8.2,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11817721/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143400791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A novel therapeutic approach targeting PD-L1 in HNSCC and bone marrow-derived mesenchymal stem cells hampers pro-metastatic features in vitro: perspectives for blocking tumor-stroma communication and signaling.
IF 8.2 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2025-02-10 DOI: 10.1186/s12964-025-02073-7
Ylenia Ferrara, Debora Latino, Angela Costagliola di Polidoro, Angela Oliver, Annachiara Sarnella, Maria Grazia Caprio, Laura Cerchia, Menotti Ruvo, Annamaria Sandomenico, Antonella Zannetti

Background: Current conventional treatment regimens for head and neck squamous cell carcinoma (HNSCC), are poorly effective because of the emergence of resistance mechanisms. Many studies have reported how the tumor microenvironment influences tumor response to immune checkpoint inhibitors targeting PD-1/PD-L1. It has been reported that overexpression of PD-L1 correlates with and is involved in cancer progression by promoting epithelial-to-mesenchymal-transition (EMT) program, stemness and tumor cell invasiveness through AKT and MAPK pathways. In this study, we investigated how bone marrow mesenchymal stem cells (BM-MSCs) recruited and educated by HNSCC cells are able to promote tumor cell invasion and EMT program. In addition, we analyzed how the crosstalk between stromal cells and tumor cells can affect PD-L1 expression levels. In this context, we developed and characterized a novel anti-PD-L1 recombinant Fab (rFab') and tested its ability to potentiate the effect of cisplatin.

Methods: BM-MSCs and HNSCC cells co-cultures, cell migration and invasion were performed using Boyden chambers. The effect of treatments on cell viability and growth were analyzed by MTT and clonogenic assay, respectively. The anti-PD-L1 rFab' was prepared in E. Coli and tested for its binding on HNSCC cells and BM-MSCs by FACS analysis and fluorescence microscopy. PD-L1, p-AKT, p-ERK, N-cadherin and β-catenin expression levels were analyzed by western blotting.

Results: BM-MSCs were induced by tumor cells to migrate, invade and to trans-differentiate in cancer associated fibroblasts (CAFs) as demonstrated by increased expression levels of α-SMA and FAP-α. BM-MSCs contributed to HNSCC invasiveness by increasing p-AKT, p-ERK, N-cadherin and β-catenin expression levels. When BM-MSCs and HNSCC cells were co-cultured the level of PD-L1 expression was enhanced in both cells indicating a reciprocal support in favoring tumor aggressiveness. Tumor cell treatment with rFab' anti-PD-L1 reduced their viability, growth, migration and invasion and blunted the underlying signaling pathways. In addition, rFab' anti-PD-L1 was able to potentiate the antitumor effect of cisplatin on HNSCC cells.

Conclusions: BM-MSCs recruited and educated by HNSCC cells support tumor cell aggressiveness via PD-L1. A novel rFab' anti-PD-L1 reduces HNSCC proliferation, migration and invasion and potentiates the cisplatin effect suggesting its potential to be conjugated with drugs for immuno-cytotoxic therapy.

{"title":"A novel therapeutic approach targeting PD-L1 in HNSCC and bone marrow-derived mesenchymal stem cells hampers pro-metastatic features in vitro: perspectives for blocking tumor-stroma communication and signaling.","authors":"Ylenia Ferrara, Debora Latino, Angela Costagliola di Polidoro, Angela Oliver, Annachiara Sarnella, Maria Grazia Caprio, Laura Cerchia, Menotti Ruvo, Annamaria Sandomenico, Antonella Zannetti","doi":"10.1186/s12964-025-02073-7","DOIUrl":"10.1186/s12964-025-02073-7","url":null,"abstract":"<p><strong>Background: </strong>Current conventional treatment regimens for head and neck squamous cell carcinoma (HNSCC), are poorly effective because of the emergence of resistance mechanisms. Many studies have reported how the tumor microenvironment influences tumor response to immune checkpoint inhibitors targeting PD-1/PD-L1. It has been reported that overexpression of PD-L1 correlates with and is involved in cancer progression by promoting epithelial-to-mesenchymal-transition (EMT) program, stemness and tumor cell invasiveness through AKT and MAPK pathways. In this study, we investigated how bone marrow mesenchymal stem cells (BM-MSCs) recruited and educated by HNSCC cells are able to promote tumor cell invasion and EMT program. In addition, we analyzed how the crosstalk between stromal cells and tumor cells can affect PD-L1 expression levels. In this context, we developed and characterized a novel anti-PD-L1 recombinant Fab (rFab') and tested its ability to potentiate the effect of cisplatin.</p><p><strong>Methods: </strong>BM-MSCs and HNSCC cells co-cultures, cell migration and invasion were performed using Boyden chambers. The effect of treatments on cell viability and growth were analyzed by MTT and clonogenic assay, respectively. The anti-PD-L1 rFab' was prepared in E. Coli and tested for its binding on HNSCC cells and BM-MSCs by FACS analysis and fluorescence microscopy. PD-L1, p-AKT, p-ERK, N-cadherin and β-catenin expression levels were analyzed by western blotting.</p><p><strong>Results: </strong>BM-MSCs were induced by tumor cells to migrate, invade and to trans-differentiate in cancer associated fibroblasts (CAFs) as demonstrated by increased expression levels of α-SMA and FAP-α. BM-MSCs contributed to HNSCC invasiveness by increasing p-AKT, p-ERK, N-cadherin and β-catenin expression levels. When BM-MSCs and HNSCC cells were co-cultured the level of PD-L1 expression was enhanced in both cells indicating a reciprocal support in favoring tumor aggressiveness. Tumor cell treatment with rFab' anti-PD-L1 reduced their viability, growth, migration and invasion and blunted the underlying signaling pathways. In addition, rFab' anti-PD-L1 was able to potentiate the antitumor effect of cisplatin on HNSCC cells.</p><p><strong>Conclusions: </strong>BM-MSCs recruited and educated by HNSCC cells support tumor cell aggressiveness via PD-L1. A novel rFab' anti-PD-L1 reduces HNSCC proliferation, migration and invasion and potentiates the cisplatin effect suggesting its potential to be conjugated with drugs for immuno-cytotoxic therapy.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"74"},"PeriodicalIF":8.2,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11809099/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143392554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Tau-tubulin kinase 2 restrains microtubule-depolymerizer KIF2A to support primary cilia growth.
IF 8.2 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2025-02-10 DOI: 10.1186/s12964-025-02072-8
David Benk Vysloužil, Ondřej Bernatík, Eva Lánská, Tereza Renzová, Lucia Binó, Andrea Lacigová, Tereza Drahošová, Zdeněk Lánský, Lukáš Čajánek

Background: Primary cilia facilitate cellular signalling and play critical roles in development, homeostasis, and disease. Their assembly is under the control of Tau-Tubulin Kinase 2 (TTBK2), a key enzyme mutated in patients with spinocerebellar ataxia. Recent work has implicated TTBK2 in the regulation of cilia maintenance and function, but the underlying molecular mechanisms are not understood.

Methods: To dissect the role of TTBK2 during cilia growth and maintenance in human cells, we examined disease-related TTBK2 truncations. We used biochemical approaches, proteomics, genetic engineering, and advanced microscopy techniques to unveil molecular events triggered by TTBK2.

Results: We demonstrate that truncated TTBK2 protein moieties, unable to localize to the mother centriole, create unique semi-permissive conditions for cilia assembly, under which cilia begin to form but fail to elongate. Subsequently, we link the defects in cilia growth to aberrant turnover of a microtubule-depolymerizing kinesin KIF2A, which we find restrained by TTBK2 phosphorylation.

Conclusions: Together, our data imply that the regulation of KIF2A by TTBK2 represents an important mechanism governing cilia elongation and maintenance. Further, the requirement for concentrating TTBK2 activity to the mother centriole to initiate ciliogenesis can be under specific conditions bypassed, revealing TTBK2 recruitment-independent functions of its key partner, CEP164.

{"title":"Tau-tubulin kinase 2 restrains microtubule-depolymerizer KIF2A to support primary cilia growth.","authors":"David Benk Vysloužil, Ondřej Bernatík, Eva Lánská, Tereza Renzová, Lucia Binó, Andrea Lacigová, Tereza Drahošová, Zdeněk Lánský, Lukáš Čajánek","doi":"10.1186/s12964-025-02072-8","DOIUrl":"10.1186/s12964-025-02072-8","url":null,"abstract":"<p><strong>Background: </strong>Primary cilia facilitate cellular signalling and play critical roles in development, homeostasis, and disease. Their assembly is under the control of Tau-Tubulin Kinase 2 (TTBK2), a key enzyme mutated in patients with spinocerebellar ataxia. Recent work has implicated TTBK2 in the regulation of cilia maintenance and function, but the underlying molecular mechanisms are not understood.</p><p><strong>Methods: </strong>To dissect the role of TTBK2 during cilia growth and maintenance in human cells, we examined disease-related TTBK2 truncations. We used biochemical approaches, proteomics, genetic engineering, and advanced microscopy techniques to unveil molecular events triggered by TTBK2.</p><p><strong>Results: </strong>We demonstrate that truncated TTBK2 protein moieties, unable to localize to the mother centriole, create unique semi-permissive conditions for cilia assembly, under which cilia begin to form but fail to elongate. Subsequently, we link the defects in cilia growth to aberrant turnover of a microtubule-depolymerizing kinesin KIF2A, which we find restrained by TTBK2 phosphorylation.</p><p><strong>Conclusions: </strong>Together, our data imply that the regulation of KIF2A by TTBK2 represents an important mechanism governing cilia elongation and maintenance. Further, the requirement for concentrating TTBK2 activity to the mother centriole to initiate ciliogenesis can be under specific conditions bypassed, revealing TTBK2 recruitment-independent functions of its key partner, CEP164.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"73"},"PeriodicalIF":8.2,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11809056/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143392555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Transcription factor XBP1s promotes endometritis-induced epithelial-mesenchymal transition by targeting MAP3K2, a key gene in the MAPK/ERK pathway.
IF 8.2 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2025-02-10 DOI: 10.1186/s12964-025-02050-0
Kangkang Gao, Mengqi Si, Xinxi Qin, Beibei Zhang, Zongjie Wang, Pengfei Lin, Huatao Chen, Aihua Wang, Yaping Jin

The epithelial-mesenchymal transition (EMT) is a biological process whereby epithelial cells are transformed into cells with a mesenchymal phenotype. The transcription factor, X-box binding protein 1 splicing variant (XBP1s) is a key regulator of the endoplasmic reticulum stress response (ERS); but the function of XBP1s in the endometritis-induced EMT process remains unclear. Here we found that uterine tissues from goats with endometritis exhibited an EMT phenotype, with a significant decrease in the epithelial cell polarity marker E-cadherin and a significant increase in the mesenchymal markers N-cadherin and vimentin. We also found that sustained LPS treatment induced EMT in goat endometrial epithelial cells (gEECs), along with ERS and XBP1s overexpression. XBP1s KO significantly inhibited LPS-induced EMT and migration in gEECs, while XBP1s overexpression showed the opposite result. CUT & Tag experiments performed on XBP1s revealed that MAP3K2 was a downstream target gene for XBP1s regulation. We also found that expression of MAP3K2 was positively correlated with XBP1s expression in uterine tissues of goats with endometritis and in gEECs. Assays for dual luciferase reporter and molecular docking indicated that XBP1s protein regulated the transcription of MAP3K2 by modulating promoter activity. The knockdown of MAP3K2 expression significantly inhibited the migration and EMT of gEECs. XBP1s and MAP3K2 significantly promoted phosphorylation of p38 and ERK, activating the MAPK/ERK pathway. Treatment with the MAPK/ERK inhibitor, PD98059, reversed the effects of XBP1s and MAP3K2 overexpression on LPS-induced EMT. The MAPK/ERK activator, DHC, reversed the effects of XBP1s KO and MAP3K2 KD on EMT.

{"title":"Transcription factor XBP1s promotes endometritis-induced epithelial-mesenchymal transition by targeting MAP3K2, a key gene in the MAPK/ERK pathway.","authors":"Kangkang Gao, Mengqi Si, Xinxi Qin, Beibei Zhang, Zongjie Wang, Pengfei Lin, Huatao Chen, Aihua Wang, Yaping Jin","doi":"10.1186/s12964-025-02050-0","DOIUrl":"10.1186/s12964-025-02050-0","url":null,"abstract":"<p><p>The epithelial-mesenchymal transition (EMT) is a biological process whereby epithelial cells are transformed into cells with a mesenchymal phenotype. The transcription factor, X-box binding protein 1 splicing variant (XBP1s) is a key regulator of the endoplasmic reticulum stress response (ERS); but the function of XBP1s in the endometritis-induced EMT process remains unclear. Here we found that uterine tissues from goats with endometritis exhibited an EMT phenotype, with a significant decrease in the epithelial cell polarity marker E-cadherin and a significant increase in the mesenchymal markers N-cadherin and vimentin. We also found that sustained LPS treatment induced EMT in goat endometrial epithelial cells (gEECs), along with ERS and XBP1s overexpression. XBP1s KO significantly inhibited LPS-induced EMT and migration in gEECs, while XBP1s overexpression showed the opposite result. CUT & Tag experiments performed on XBP1s revealed that MAP3K2 was a downstream target gene for XBP1s regulation. We also found that expression of MAP3K2 was positively correlated with XBP1s expression in uterine tissues of goats with endometritis and in gEECs. Assays for dual luciferase reporter and molecular docking indicated that XBP1s protein regulated the transcription of MAP3K2 by modulating promoter activity. The knockdown of MAP3K2 expression significantly inhibited the migration and EMT of gEECs. XBP1s and MAP3K2 significantly promoted phosphorylation of p38 and ERK, activating the MAPK/ERK pathway. Treatment with the MAPK/ERK inhibitor, PD98059, reversed the effects of XBP1s and MAP3K2 overexpression on LPS-induced EMT. The MAPK/ERK activator, DHC, reversed the effects of XBP1s KO and MAP3K2 KD on EMT.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"72"},"PeriodicalIF":8.2,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11808991/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143392556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
ANO7 expression in the prostate modulates mitochondrial function and lipid metabolism.
IF 8.2 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2025-02-08 DOI: 10.1186/s12964-025-02081-7
Christoffer Löf, Nasrin Sultana, Neha Goel, Samuel Heron, Gudrun Wahlström, Andrew House, Minna Holopainen, Reijo Käkelä, Johanna Schleutker

Background: Prostate cancer (PrCa) is a significant health concern, ranking as the second most common cancer in males globally. Genetic factors contribute substantially to PrCa risk, with up to 57% of the risk being attributed to genetic determinants. A major challenge in managing PrCa is the early identification of aggressive cases for targeted treatment, while avoiding unnecessary interventions in slow-progressing cases. Therefore, there is a critical need for genetic biomarkers that can distinguish between aggressive and non-aggressive PrCa cases. Previous research, including our own, has shown that germline variants in ANO7 are associated with aggressive PrCa. However, the function of ANO7 in the prostate remains unknown.

Methods: We performed RNA-sequencing (RNA-seq) on RWPE1 cells engineered to express ANO7 protein, alongside the analysis of a single-cell RNA-sequencing (scRNA-seq) dataset and RNA-seq from prostate tissues. Differential gene expression analysis and gene set enrichment analysis (GSEA) were conducted to identify key pathways. Additionally, we assessed oxidative phosphorylation (OXPHOS), glycolysis, and targeted metabolomics. Image analysis of mitochondrial morphology and lipidomics were also performed to provide further insight into the functional role of ANO7 in prostate cells.

Results: ANO7 expression resulted in the downregulation of metabolic pathways, particularly genes associated with the MYC pathway and oxidative phosphorylation (OXPHOS) in both prostate tissue and ANO7-expressing cells. Measurements of OXPHOS and glycolysis in the ANO7-expressing cells revealed a metabolic shift towards glycolysis. Targeted metabolomics showed reduced levels of the amino acid aspartate, indicating disrupted mitochondrial function in the ANO7-expressing cells. Image analysis demonstrated altered mitochondrial morphology in these cells. Additionally, ANO7 downregulated genes involved in fatty acid metabolism and induced changes in lipid composition of the cells, characterized by longer acyl chain lengths and increased unsaturation, suggesting a role for ANO7 in regulating lipid metabolism in the prostate.

Conclusions: This study provides new insights into the function of ANO7 in prostate cells, highlighting its involvement in metabolic pathways, particularly OXPHOS and lipid metabolism. The findings suggest that ANO7 may act as a key regulator of cellular lipid metabolism and mitochondrial function in the prostate, shedding light on a previously unknown aspect of ANO7's biology.

{"title":"ANO7 expression in the prostate modulates mitochondrial function and lipid metabolism.","authors":"Christoffer Löf, Nasrin Sultana, Neha Goel, Samuel Heron, Gudrun Wahlström, Andrew House, Minna Holopainen, Reijo Käkelä, Johanna Schleutker","doi":"10.1186/s12964-025-02081-7","DOIUrl":"10.1186/s12964-025-02081-7","url":null,"abstract":"<p><strong>Background: </strong>Prostate cancer (PrCa) is a significant health concern, ranking as the second most common cancer in males globally. Genetic factors contribute substantially to PrCa risk, with up to 57% of the risk being attributed to genetic determinants. A major challenge in managing PrCa is the early identification of aggressive cases for targeted treatment, while avoiding unnecessary interventions in slow-progressing cases. Therefore, there is a critical need for genetic biomarkers that can distinguish between aggressive and non-aggressive PrCa cases. Previous research, including our own, has shown that germline variants in ANO7 are associated with aggressive PrCa. However, the function of ANO7 in the prostate remains unknown.</p><p><strong>Methods: </strong>We performed RNA-sequencing (RNA-seq) on RWPE1 cells engineered to express ANO7 protein, alongside the analysis of a single-cell RNA-sequencing (scRNA-seq) dataset and RNA-seq from prostate tissues. Differential gene expression analysis and gene set enrichment analysis (GSEA) were conducted to identify key pathways. Additionally, we assessed oxidative phosphorylation (OXPHOS), glycolysis, and targeted metabolomics. Image analysis of mitochondrial morphology and lipidomics were also performed to provide further insight into the functional role of ANO7 in prostate cells.</p><p><strong>Results: </strong>ANO7 expression resulted in the downregulation of metabolic pathways, particularly genes associated with the MYC pathway and oxidative phosphorylation (OXPHOS) in both prostate tissue and ANO7-expressing cells. Measurements of OXPHOS and glycolysis in the ANO7-expressing cells revealed a metabolic shift towards glycolysis. Targeted metabolomics showed reduced levels of the amino acid aspartate, indicating disrupted mitochondrial function in the ANO7-expressing cells. Image analysis demonstrated altered mitochondrial morphology in these cells. Additionally, ANO7 downregulated genes involved in fatty acid metabolism and induced changes in lipid composition of the cells, characterized by longer acyl chain lengths and increased unsaturation, suggesting a role for ANO7 in regulating lipid metabolism in the prostate.</p><p><strong>Conclusions: </strong>This study provides new insights into the function of ANO7 in prostate cells, highlighting its involvement in metabolic pathways, particularly OXPHOS and lipid metabolism. The findings suggest that ANO7 may act as a key regulator of cellular lipid metabolism and mitochondrial function in the prostate, shedding light on a previously unknown aspect of ANO7's biology.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"71"},"PeriodicalIF":8.2,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11807338/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143375046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
β2 integrin regulates neutrophil trans endothelial migration following traumatic brain injury.
IF 8.2 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2025-02-08 DOI: 10.1186/s12964-025-02071-9
Lei Li, Ruilong Peng, Cong Wang, Xin Chen, Dilmurat Gheyret, Siyu Guan, Bo Chen, Yafan Liu, Xilei Liu, Yiyao Cao, Cha Han, Jianhua Xiong, Fanjian Li, Taoyuan Lu, Haoran Jia, Kaiji Li, Jinchao Wang, Xu Zhang, Jianye Xu, Yajuan Wang, Xin Xu, Tuo Li, Jianning Zhang, Shu Zhang

Neutrophils are the first responders among peripheral immune cells to infiltrate the central nervous system following a traumatic brain injury (TBI), triggering neuroinflammation that can exacerbate secondary tissue damage. The precise molecular controls that dictate the inflammatory behavior of neutrophils post-TBI, however, remain largely elusive. Our comprehensive analysis of the molecular landscape surrounding the trauma in TBI mice has revealed a significant alteration in the abundance of β2 integrin (ITGB2), predominantly expressed by neutrophils and closely associated with immune responses. Using the fluid percussion injury (FPI) mouse model, we investigated the therapeutic efficacy of Rovelizumab, an agent that blocks ITGB2. The treatment has demonstrated significant improvements in neurologic function in TBI mice, attenuating blood-brain barrier permeability, mitigating oxidative stress and inflammatory mediator release, and enhancing cerebral perfusion. Moreover, ITGB2 blockade has effectively limited the adherence, migration, and infiltration of neutrophils, and has impeded the formation of neutrophil extracellular traps (NETs) upon their activation. Finally, it was demonstrated that ITGB2 mediates these effects mainly through its interaction with intercellular adhesion molecule-1 (ICAM 1) of endotheliocyte. These findings collectively illuminate ITGB2 as a crucial molecular switch that governs the adverse effects of neutrophils post-TBI and could be targeted to improve clinical outcome in patients.

{"title":"β2 integrin regulates neutrophil trans endothelial migration following traumatic brain injury.","authors":"Lei Li, Ruilong Peng, Cong Wang, Xin Chen, Dilmurat Gheyret, Siyu Guan, Bo Chen, Yafan Liu, Xilei Liu, Yiyao Cao, Cha Han, Jianhua Xiong, Fanjian Li, Taoyuan Lu, Haoran Jia, Kaiji Li, Jinchao Wang, Xu Zhang, Jianye Xu, Yajuan Wang, Xin Xu, Tuo Li, Jianning Zhang, Shu Zhang","doi":"10.1186/s12964-025-02071-9","DOIUrl":"10.1186/s12964-025-02071-9","url":null,"abstract":"<p><p>Neutrophils are the first responders among peripheral immune cells to infiltrate the central nervous system following a traumatic brain injury (TBI), triggering neuroinflammation that can exacerbate secondary tissue damage. The precise molecular controls that dictate the inflammatory behavior of neutrophils post-TBI, however, remain largely elusive. Our comprehensive analysis of the molecular landscape surrounding the trauma in TBI mice has revealed a significant alteration in the abundance of β2 integrin (ITGB2), predominantly expressed by neutrophils and closely associated with immune responses. Using the fluid percussion injury (FPI) mouse model, we investigated the therapeutic efficacy of Rovelizumab, an agent that blocks ITGB2. The treatment has demonstrated significant improvements in neurologic function in TBI mice, attenuating blood-brain barrier permeability, mitigating oxidative stress and inflammatory mediator release, and enhancing cerebral perfusion. Moreover, ITGB2 blockade has effectively limited the adherence, migration, and infiltration of neutrophils, and has impeded the formation of neutrophil extracellular traps (NETs) upon their activation. Finally, it was demonstrated that ITGB2 mediates these effects mainly through its interaction with intercellular adhesion molecule-1 (ICAM 1) of endotheliocyte. These findings collectively illuminate ITGB2 as a crucial molecular switch that governs the adverse effects of neutrophils post-TBI and could be targeted to improve clinical outcome in patients.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"70"},"PeriodicalIF":8.2,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11806581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Nano-XRF of lung fibrotic tissue reveals unexplored Ca, Zn, S and Fe metabolism: a novel approach to chronic lung diseases. 肺纤维化组织的纳米 XRF 揭示了尚未探索的钙、锌、硒和铁代谢:一种治疗慢性肺病的新方法。
IF 8.2 2区 生物学 Q1 CELL BIOLOGY Pub Date : 2025-02-07 DOI: 10.1186/s12964-025-02076-4
Bryan Falcones, Maik Kahnt, Ulf Johansson, Barbora Svobodová, Karin A von Wachenfelt, Charlott Brunmark, Göran Dellgren, Linda Elowsson, Karina Thånell, Gunilla Westergren-Thorsson

Synchrotron-radiation nano-X-Ray Fluorescence (XRF) is a cutting-edge technique offering high-resolution insights into the elemental composition of biological tissues, shedding light on metabolic processes and element localization within cellular structures. In the context of Idiopathic Pulmonary Fibrosis (IPF), a debilitating lung condition associated with respiratory complications and reduced life expectancy, nano-XRF presents a promising avenue for understanding the disease's intricate pathology. Our developed workflow enables the assessment of elemental composition in both human and rodent fibrotic tissues, providing insights on the interplay between cellular compartments in chronic lung diseases. Our findings demonstrate trace element accumulations associated with anthracosis, a feature observed in IPF. Notably, Zn and Ca clusters approximately 750 nm in size were identified exclusively in IPF samples. While their specific role remains unclear, their presence may be associated with disease-specific processes. Additionally, we observed Fe and S signal colocalization in 650-nm structures within some IPF cells. Fe-S complexes in mitochondria are known to be associated with increased ROS production, suggesting a potential connection to the disease pathology. In contrast, a bleomycin-induced fibrosis rodent model exhibits a different elemental phenotype with low Fe and increased S, Zn, and Ca. Overall, our workflow highlights the effectiveness of synchrotron-based nano-XRF mapping in analyzing the spatial distribution of trace elements within diseased tissue, offering valuable insights into the elemental aspects of IPF and related chronic lung diseases.

{"title":"Nano-XRF of lung fibrotic tissue reveals unexplored Ca, Zn, S and Fe metabolism: a novel approach to chronic lung diseases.","authors":"Bryan Falcones, Maik Kahnt, Ulf Johansson, Barbora Svobodová, Karin A von Wachenfelt, Charlott Brunmark, Göran Dellgren, Linda Elowsson, Karina Thånell, Gunilla Westergren-Thorsson","doi":"10.1186/s12964-025-02076-4","DOIUrl":"10.1186/s12964-025-02076-4","url":null,"abstract":"<p><p>Synchrotron-radiation nano-X-Ray Fluorescence (XRF) is a cutting-edge technique offering high-resolution insights into the elemental composition of biological tissues, shedding light on metabolic processes and element localization within cellular structures. In the context of Idiopathic Pulmonary Fibrosis (IPF), a debilitating lung condition associated with respiratory complications and reduced life expectancy, nano-XRF presents a promising avenue for understanding the disease's intricate pathology. Our developed workflow enables the assessment of elemental composition in both human and rodent fibrotic tissues, providing insights on the interplay between cellular compartments in chronic lung diseases. Our findings demonstrate trace element accumulations associated with anthracosis, a feature observed in IPF. Notably, Zn and Ca clusters approximately 750 nm in size were identified exclusively in IPF samples. While their specific role remains unclear, their presence may be associated with disease-specific processes. Additionally, we observed Fe and S signal colocalization in 650-nm structures within some IPF cells. Fe-S complexes in mitochondria are known to be associated with increased ROS production, suggesting a potential connection to the disease pathology. In contrast, a bleomycin-induced fibrosis rodent model exhibits a different elemental phenotype with low Fe and increased S, Zn, and Ca. Overall, our workflow highlights the effectiveness of synchrotron-based nano-XRF mapping in analyzing the spatial distribution of trace elements within diseased tissue, offering valuable insights into the elemental aspects of IPF and related chronic lung diseases.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"23 1","pages":"67"},"PeriodicalIF":8.2,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11806689/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143371280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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Cell Communication and Signaling
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