Effect of CAR-M2 hydrogel treatment on the expression of related genes such as fibrosis and endothelial angiogenesis in mice with renal fibrosis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE252943 | GEO | 2026/02/06
REPOSITORIES: GEO
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Project description:Currently there is no effective treatment for renal fibrosis, which is the common outcome of chronic kidney disease (CKD). The renal fibrosis was aggravated by the unfavorable microenvironment and cell-to-cell interactions, accompanied by fibroblast activation and vascular rarefaction. Here, M2 macrophage engineered with chimeric antigen receptor (CAR) was created to promote renal revascularization for the synergistic treatment of phagocytosis of activated fibroblast. To achieve efficient delivery of parenchymal organs, a hydrogel was used to deliver CAR-M2 by renal subcapsule injection. CAR-M2 significantly reduced renal fibrosis and promoted revascularization. The single-cell RNA sequencing (scRNA-seq) revealed the heterogenicity and interaction of stroma and endothelial cells (ECs). A fibrosis-related Cxcr2+ EC subset was defined, which induced renal fibrosis by upregulating lipocalin 2 (Lcn2). Combined analysis of CKD patients demonstrated that CAR-M2 could release Matrix Metalloproteinase 2 (MMP2) in close proximity to activate the Cxcr2+ EC retinoid X receptor alpha (Rxra) to regulate fibrosis. Our study provides an effective strategy to develop an advanced cell therapy for organ fibrosis.
2026-02-06 | GSE282078 | GEO
Project description:Liver fibrosis is a common pathological process in chronic liver disease, reflecting the advanced stage of the disease. Liver endothelial cells (ECs), especially liver sinusoidal endothelial cells (LSECs), are recognized as critical modulators of liver homeostasis and play essential roles in the recruitment and function of liver immune cells. However, the mechanism of liver EC injury and the occurrence of intercellular crosstalk in liver fibrosis are still unclear. In this study, C57BL/6 male mice were treated with CCl4 for 6 weeks to establish a liver fibrosis model. Masson staining and immunohistochemistry were performed to assess the extent of liver fibrosis. Liver endothelial injury was detected by using scanning electron microscopy (SEM) and PCR technology. Single-cell RNA sequencing (scRNA-seq) was performed to analyze phenotypic changes in nonparenchymal cells and dissect intercellular crosstalk in liver fibrosis. A total of 24,534 cells were analyzed and clustered into 10 main cell subsets. Liver ECs decreased significantly, and macrophage recruitment increased in the CCl4 group. The LSEC fenestrae and surface receptors expression were reduced, and the expression of Cd34 was upregulated. Liver ECs exhibited dense cellular crosstalk with immune cells such as macrophages, T cells, and B cells. The analysis of intercellular signaling pathways revealed that immune cells targeted liver ECs through the Ptprc-Mrc1 and Sell-Podxl signaling pathways to maintain intercellular interactions during liver fibrosis. We described the single-cell landscape of a liver fibrosis mouse model and demonstrated the presence of tight intracellular crosstalk between ECs with macrophages, T, and B cells, revealing cell-cell communications among liver immune cells-ECs during the process of liver fibrosis. The Ptprc-Mrc1 and Sell-Podxl signaling pathways exerted prominent roles in the interaction between immune cells and liver ECs.
2025-06-01 | GSE268846 | GEO
Project description:The aim of this study was to investigate the role of infiltrating macrophages in renal allograft fibrosis. Forty-six protocol renal allograft biopsies obtained one-year after transplantation were stained with Sirius Red to quantify fibrosis and double stained with CD68 and CD206 to identify the proportion of alternately activated (M2) macrophages. 23 protocol biopsies obtained 12 months post transplant were analyzed for gene expression by microarray, which was correlated with macrophage infiltration and the severity of fibrosis. Phenotypic analysis showed 92% of infiltrating macrophages exhibited an M2 phenotype with CD68+CD206+ dual staining. Gene microarrays demonstrated a distinct alloimmune response despite the lack of rejection and inflammatory infiltrate with upregulation of interferon-γ-response genes. This suggests that following initiation of Th1 driven macrophage proliferation or infiltration, M2 macrophages contribute to tubular injury and progression of fibrosis. 23 protocol renal biopsies were obtained from patients at 12 month post transplant. The study population was divided into two groups according to the number of infiltrating macrophages (CD68 positive cells) (Group I: Recipients with a low number of infiltrating macrophages, CD68 positive cells < 400/mm2; Group II: Recipients with a high number of infiltrating macrophages, CD68 positive cells ≥ 400/mm2). Additional analyses were undertaken by dividing the group into those with fibrosis (ci score >1) and those without. To correlate gene expression with kidney fibrosis, or intensity of CD68 infiltrate, Spearman correlations analysis of the gene expression data with 12 month IFTA was performed and the correlation co-efficiency and its p value calculated. Gene Ontology enrichment and IPA pathway and network analysis (Ingenuity System Inc.) were performed on the associated genes. All p-values were two-sided, and p < 0.05 was considered significant.
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Project description:Excessive renal fibrosis is a common pathology in progressive chronic kidney diseases. Inflammatory injury and aberrant repair processes contribute to the development of kidney fibrosis. Myeloid cells, particularly monocytes/macrophages, play a crucial role in kidney fibrosis by releasing their proinflammatory cytokines and extracellular matrix components such as collagen and fibronectin into the microenvironment of the injured kidney. Numerous signaling pathways have been identified in relation to these activities. However, the involvement of metabolic pathways in myeloid cell functions during the development of renal fibrosis remains understudied. In our study, we initially reanalyzed single-cell RNA sequencing data of renal myeloid cells from Dr. Denby’s group and observed an increased glycolytic pathway in myeloid cells that are critical for renal inflammation and fibrosis. To investigate the role of myeloid glycolysis in renal fibrosis, we utilized a model of unilateral ureteral obstruction in mice deficient of Pfkfb3, an activator of glycolysis, in myeloid cells (Pfkfb3ΔMϕ) and their wild type littermates (Pfkfb3WT). We observed a significant reduction in fibrosis in the obstructive kidneys of Pfkfb3ΔMϕ mice compared to Pfkfb3WT mice. This was accompanied by a substantial decrease in myeloid cell infiltration, as well as a decrease in the numbers of M1 and M2 macrophages and suppression of macrophage to obtain myofibroblast phenotype in the obstructive kidneys of Pfkfb3ΔMϕ mice. Mechanistic studies indicate that glycolytic metabolites stabilize HIF1α, leading to alterations in macrophage phenotypes that contribute to renal fibrosis. In conclusion, our study implicates that targeting myeloid glycolysis represents a novel approach to inhibit renal fibrosis.
2024-03-12 | MTBLS8278 | MetaboLights
Project description:Numerous studies have proven the critical role of macrophages in the renal fibrosis process. Notably, G Protein-coupled Estrogen Receptor 1 (GPER1), a novel estrogen receptor, has been shown to play a ubiquitous role in the regulation of macrophage activities and proinflammatory pathways. However, the precise role of GPER1 in macrophage-mediated renal fibrosis is unknown. In this study, we aimed to investigate the function of macrophage GPER1 in the UUO-induced renal fibrosis model. Compared to vehicle-treated ovariectomized (OVX) female and male UUO models, we observed that G-1 (GPER1 agonist)-treated OVX female and male UUO mice had fewer renal fibrotic lesions and less M1 and M2 macrophage infiltration in the kidney tissues. Conversely, Gper1 deletion in male UUO mice accelerated renal fibrosis and increased inflammation. In vitro studies also revealed that GPER1 activation reduced M0 macrophage polarization towards M1 and M2 phenotypes. The RNA sequencing analysis and immunoblotting indicated that GPER1 activation was primarily involved in downregulating immune pathways activation and inactivating MAPK pathways. Tubular epithelial cells co-cultured with G1-pretreated M1 macrophages exhibited fewer injuries and immune activation. In addition, fibroblasts co-cultured with G1-pretreated M2 macrophages showed downregulated extracellular matrix expression. Overall, this is the first study to demonstrate the effect of GPER1 on macrophage-mediated renal fibrosis via inhibition of M1 and M2 macrophage polarization. These findings indicate that GPER1 may be a promising therapeutic target for the treatment of renal fibrosis.
2023-12-20 | GSE235718 | GEO
Project description:Macrophages are recognized as the vital players in renal fibrosis, with a high degree of heterogeneity and plasticity, and triggering receptor expressed on myeloid cell-2(TREM-2) was highly expressed on macrophages and participated in the progression of tissue fibrosis. However, the mechanism by which TREM-2 mediate the progress of renal fibrosis is still unclear. Our study have found the exosomes derived from TREM-2 deficient (TREM-2-/-) macrophages could suppress the progression of fibrosis, showing a higher matrix metalloproteinase-9 (MMP-9) / tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) ration at protein level in secreted exosomes than exosomes from WT（wild type）macrophages in the fibrotic microenvironment. Besides, renal tubular epithelial cells (TECs) engulfed theses nanoscale vesicles, the expression of collagen I and α-smooth muscle actin (α-SMA) (fibrosis related marker) was obviously decreased. Through the RNA-seq, we found that TREM-2-/- macrophages upregulate the MMP-9/TIMP-1 ratio in its exosomes via HSPa1b/AKT pathway. Furthermore, it’s noteworthy that the renal fibrosis was effectively alleviated in the obstructed kidney from mice received a renal pelvis injection of adeno associated virus (AAV-shTREM-2) containing the sequence of silencing TREM-2. However, VER-155008 (inhibitor of HSPa1b) and Ly294002 (inhibitor of AKT) reversed this effect. Moreover, polyclonal antibodies against TREM-2 also effectively relieved the UUO-induced renal fibrosis. Above all, we have validated that the knocking down TREM-2 expression can inhibit the progression of renal fibrosis through a macrophage exosome-dependent pathway in vitro and vivo. Hence, our finding suggest TREM-2 is potential therapeutic target for CKD.
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Project description:Renal fibrosis is a key pathological feature of chronic kidney disease, and non-alcoholic fatty liver disease (NAFLD) is associated with its progression. Our previous experimental results indicate that NAFLD exacerbates UUO-induced renal fibrosis. However, the specific role and mechanisms of NAFLD in renal fibrosis remain unclear. To further investigate the underlying mechanisms, we used single-cell transcriptome sequencing to construct a single-cell atlas of the kidney. Single-cell RNA sequencing analysis and our further experimental results showed that high-fat-induced hepatocytes releasing significant levels of ANGPTL8, which activates renal CCR2+PIRB+ macrophages. These specialized macrophages promote the activation and proliferation of Th17 cells, which could further worsen renal fibrosis. The ANGPTL8/PIRB/ALOX5AP axis is thus a crucial signaling pathway between the liver and kidneys, with CCR2+PIRB+ macrophages playing a pivotal role in the progression of NAFLD-induced renal fibrosis.
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Project description:Fibrosis, or scarring, can affect many organs including liver, lung, heart, kidney, intestines etc. and contributes to ~40% of mortality in the industrialized world. Unlike other organs, fibrosis in the liver typically resolves when the source of injury is extinguished. Elucidating the molecular mechanisms that underlie spontaneous fibrosis resolution may lead to novel antifibrotic strategies. In this study we established a robust mouse model of fibrosis regression in MASH (Metabolic dysfunction-Associated Steatohepatitis), a highly prevalent chronic liver disease worldwide, and performed single cell and in situ molecular profiling to define the molecular drivers of fibrosis regression. As fibrosis regressed, inflammatory cell numbers decreased and endothelial cell (EC) numbers increased. Prediction of cell-cell communication using the Calligraphy pipeline identified a Wnt9b-Sfrp2 crosstalk that emerged as fibrosis resolved. To investigate the Wnt9b-Sfrp2 crosstalk as a driver of fibrosis resolution we treated mice with recombinant SFRP2, a WNT inhibitor, which attenuated spontaneous fibrosis regression compared to vehicle-treated mice. Using single nucleus RNA sequencing, we identified a subset of liver ECs termed ‘Endo4’, as the source of Wnt9b. Immunostaining of the Endo4 marker VWF using tissue clearing and 3D imaging identified VWF+ vasculature surrounded by activated hepatic stellate cells (HSCs) that penetrated deep into the fibrotic septa, establishing them as de facto scar-associated ECs. Functionally, using a novel in situ protease activity-based probes, prominent serine protease activity was found to be co-localized with both scar-associated Endo4 ECs and HSCs. In summary, WNT-dependent endo-stellate crosstalk within the fibrotic niche represents a novel regulatory node in murine MASH fibrosis regression and a promising therapeutic target.
2025-12-20 | GSE306327 | GEO
Project description:Fibrosis, or scarring, can affect many organs including liver, lung, heart, kidney, intestines etc. and contributes to ~40% of mortality in the industrialized world. Unlike other organs, fibrosis in the liver typically resolves when the source of injury is extinguished. Elucidating the molecular mechanisms that underlie spontaneous fibrosis resolution may lead to novel antifibrotic strategies. In this study we established a robust mouse model of fibrosis regression in MASH (Metabolic dysfunction-Associated Steatohepatitis), a highly prevalent chronic liver disease worldwide, and performed single cell and in situ molecular profiling to define the molecular drivers of fibrosis regression. As fibrosis regressed, inflammatory cell numbers decreased and endothelial cell (EC) numbers increased. Prediction of cell-cell communication using the Calligraphy pipeline identified a Wnt9b-Sfrp2 crosstalk that emerged as fibrosis resolved. To investigate the Wnt9b-Sfrp2 crosstalk as a driver of fibrosis resolution we treated mice with recombinant SFRP2, a WNT inhibitor, which attenuated spontaneous fibrosis regression compared to vehicle-treated mice. Using single nucleus RNA sequencing, we identified a subset of liver ECs termed ‘Endo4’, as the source of Wnt9b. Immunostaining of the Endo4 marker VWF using tissue clearing and 3D imaging identified VWF+ vasculature surrounded by activated hepatic stellate cells (HSCs) that penetrated deep into the fibrotic septa, establishing them as de facto scar-associated ECs. Functionally, using a novel in situ protease activity-based probes, prominent serine protease activity was found to be co-localized with both scar-associated Endo4 ECs and HSCs. In summary, WNT-dependent endo-stellate crosstalk within the fibrotic niche represents a novel regulatory node in murine MASH fibrosis regression and a promising therapeutic target.
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