Discovery of a Novel Class of Bioactive Molecules Suppressing Pathogenic Fibroblast Activation through Hyou1 Targeting
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE237395 | GEO | 2024/03/12
REPOSITORIES: GEO
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Project description:The central nervous system (CNS) is surrounded by three membranes called meninges. Specialized fibroblasts, originating from the mesoderm and neural crest, primarily populate the meninges and serve as a binding agent. Our goal was to compare fibroblasts from meninges and skin obtained from the same human-aged donors, exploring their molecular and cellular characteristics related to CNS functions. We isolated meningeal fibroblasts (MFs) and skin fibroblasts (SFs) from brain donors. A functional analysis was performed measuring cell appearance, metabolic activity, and cellular orientation. We examined fibronectin, serpin H1, β-III-tubulin, and nestin through qPCR and immunofluorescence. A whole transcriptome analysis was also performed to characterize the gene expression of MFs and SFs. MFs appeared more rapidly post-tissue processing, while SFs have an elevated cellular metabolism and a well-defined cellular orientation. The four markers were mostly similar between the MFs and SFs, except for nestin, more expressed in MFs. Transcriptome analysis reveals significant differences, particularly in cyclic adenosine monophosphate (cAMP) metabolism and response to forskolin, both of which are upregulated in MFs. This study highlights MFs' unique characteristics, such as the timing of appearance, metabolic activity, and gene expression patterns, particularly in cAMP metabolism and response to forskolin. These findings contribute to a deeper understanding of non-neuronal cells' involvement in CNS activities and potentially open avenues for therapeutic exploration.
2024-02-29 | GSE255684 | GEO
Project description:Background: Tumor metastasis is a major threat to cancer patient survival. The organ-specific niche plays a pivotal role in tumor organotropic metastasis. Fibroblasts serve as a vital component of the metastatic microenvironment, but how heterogeneous metastasis-associated fibroblasts (MAFs) promote organotropic metastasis is poorly characterized. Here, we aimed to decipher the heterogeneity of MAFs and elucidate the distinct roles of these fibroblasts in pulmonary metastasis formation in breast cancer. Methods: Mouse models of breast cancer pulmonary metastasis were established using an in vivo selection method of repeated injections of metastatic cells purified from the mouse lung. Single-cell RNA sequencing (scRNA-seq) was employed to investigate the heterogeneity of MAFs. Transgenic mice were used to examine the contribution of tryptophan 2, 3-dioxygenase positive matrix fibroblasts (TDO2+ MFs) in lung metastasis.. Results: We uncovered three subtypes of MAFs in the lung metastatic microenvironment and their transcriptome profiles changed dynamically as lung metastasis evolves. As the predominant subtype, matrix fibroblasts (MFs) were exclusively marked by platelet-derived growth factor receptor alpha (PDGFRA) and mainly located on the edge of the metastasis, and T cells were enriched around MFs. Notably, high MFs signatures were significantly associated with poor survival in breast cancer patients. Lung metastases were markedly diminished and the suppression of T cells was dramatically attenuated in MF-depleted experimental metastatic mouse models. We found that TDO2+ MFs control pulmonary metastasis by producing kynurenine (KYN), which upregulated FTH1 level in disseminated tumor cells (DTCs), enabling DTCs to resist ferroptosis. Moreover, TDO2+ MFs-secreted the chemokines CCL8 and CCL11 recruited T cells. TDO2+ MF-derived KYN induced T cell dysfunction. Conditional knockout of Tdo2 in MFs diminished lung metastasis and enhanced immune activation. Conclusions: Our study reveals crucial roles of TDO2+ MFs in promoting lung metastasis and DTCs' immune evasion in the metastatic niche. It suggests that targeting the metabolism of lung-specific stromal cells may be an effective treatment strategy for breast cancer patients with lung metastasis.
2024-06-21 | GSE270152 | GEO
Project description:Background: Tumor metastasis is a major threat to cancer patient survival. The organ-specific niche plays a pivotal role in tumor organotropic metastasis. Fibroblasts serve as a vital component of the metastatic microenvironment, but how heterogeneous metastasis-associated fibroblasts (MAFs) promote organotropic metastasis is poorly characterized. Here, we aimed to decipher the heterogeneity of MAFs and elucidate the distinct roles of these fibroblasts in pulmonary metastasis formation in breast cancer. Methods: Mouse models of breast cancer pulmonary metastasis were established using an in vivo selection method of repeated injections of metastatic cells purified from the mouse lung. Single-cell RNA sequencing (scRNA-seq) was employed to investigate the heterogeneity of MAFs. Transgenic mice were used to examine the contribution of tryptophan 2, 3-dioxygenase positive matrix fibroblasts (TDO2+ MFs) in lung metastasis.. Results: We uncovered three subtypes of MAFs in the lung metastatic microenvironment and their transcriptome profiles changed dynamically as lung metastasis evolves. As the predominant subtype, matrix fibroblasts (MFs) were exclusively marked by platelet-derived growth factor receptor alpha (PDGFRA) and mainly located on the edge of the metastasis, and T cells were enriched around MFs. Notably, high MFs signatures were significantly associated with poor survival in breast cancer patients. Lung metastases were markedly diminished and the suppression of T cells was dramatically attenuated in MF-depleted experimental metastatic mouse models. We found that TDO2+ MFs control pulmonary metastasis by producing kynurenine (KYN), which upregulated FTH1 level in disseminated tumor cells (DTCs), enabling DTCs to resist ferroptosis. Moreover, TDO2+ MFs-secreted chemokines CCL8 and CCL11 recruited T cells. TDO2+ MF-derived KYN induced T cell dysfunction. Conditional knockout of Tdo2 in MFs diminished lung metastasis and enhanced immune activation. Conclusions: Our study reveals crucial roles of TDO2+ MFs in promoting lung metastasis and DTCs' immune evasion in the metastatic niche. It suggests that targeting the metabolism of lung-specific stromal cells may be an effective treatment strategy for breast cancer patients with lung metastasis.
2024-06-18 | GSE269817 | GEO
Project description:We developed in vivo reprogramming of myofibroblasts (MFs) into induced hepatocytes (MF-iHeps) using adeno-associated virus serotype 6 (AAV6) vectors expressing hepatic transcription factors in MF fate tracing (Lrat-Cre;R26R-ZsGreen) mice with carbon tetrachloride (CCl4)-induced liver fibrosis. To determine whether MF-iHeps acquire full hepatocyte differentiation, we used microarrays to profile their global gene expression. We isolated MF-iHeps and primary hepatocytes (Heps) from the same mice by laser-capture microdissection (5 and 3 biological replicates, respectively) and hepatic MFs from CCl4-treated littermates isolated by fluorescence-activated cell sorting (3 biological replicates). Total RNA was extracted, transcribed, amplified and biotin labeled. Labeled cDNA targets were hybridized to GeneChip Mouse Gene 1.0 ST arrays (Affymetrix).
2016-05-17 | E-GEOD-81491 | biostudies-arrayexpress
Project description:The etiology of non-alcoholic fatty liver disease (NAFLD) is poorly understood, with males and Mexican population exhibiting markedly increased susceptibility. Using a systems genetics approach, involving multi-omic analysis of ~100 inbred strains, we recently identified several candidate genes driving NAFLD. We investigated the role of one of these candidates, liver pyruvate kinase (L-PK or Pklr) in NAFLD using patient samples and mouse models. We examined L-PK expression in mice of both sexes and in a cohort of bariatric surgery patients. We used liver-specific loss- and gain-of-function strategies in independent animal models of diet-induced steatosis and fibrosis, involving both sexes. Following treatment, we measured several metabolic phenotypes associated with obesity, insulin resistance, dyslipidemia, liver steatosis and fibrosis. Furthermore, liver tissues were used for gene expression and Western blots, and liver mitochondria for bioenergetics. Our results demonstrate that L-PK acts in a male-specific manner in the development of liver steatosis and fibrosis. Given that NAFLD/NASH exhibit sexual dimorphism, our results have important implications for the development of personalized therapeutics.
2021-01-19 | GSE157201 | GEO
Project description:The etiology of non-alcoholic fatty liver disease (NAFLD) is poorly understood, with males and Mexican population exhibiting markedly increased susceptibility. Using a systems genetics approach, involving multi-omic analysis of ~100 inbred strains, we recently identified several candidate genes driving NAFLD. We investigated the role of one of these candidates, liver pyruvate kinase (L-PK or Pklr) in NAFLD using patient samples and mouse models. We examined L-PK expression in mice of both sexes and in a cohort of bariatric surgery patients. We used liver-specific loss- and gain-of-function strategies in independent animal models of diet-induced steatosis and fibrosis, involving both sexes. Following treatment, we measured several metabolic phenotypes associated with obesity, insulin resistance, dyslipidemia, liver steatosis and fibrosis. Furthermore, liver tissues were used for gene expression and western blots, and liver mitochondria for bioenergetics. Our results demonstrate that L-PK acts in a male-specific manner in the development of liver steatosis and fibrosis. Given that NAFLD/NASH exhibit sexual dimorphism, our results have important implications for the development of personalized therapeutics.
2021-01-19 | GSE151182 | GEO
Project description:Background: Marfan syndrome (MFS) is a heritable connective tissue disorder caused by mutations in the fibrillin-1 gene. This syndrome constitutes a significant identifiable subtype of aortic aneurysmal disease, accounting for over 5% of ascending and thoracic aortic aneurysms. Results: We used spotted membrane DNA macroarrays to identify genes whose altered expression levels may contribute to the phenotype of the disease. Our analysis of 4132 genes identified a subset with significant expression differences between skin fibroblast cultures from unaffected controls versus cultures from affected individuals with known fibrillin-1 mutations. Subsequently, 10 genes were chosen for validation by quantitative RT-PCR. Conclusions: Differential expression of many of the validated genes was associated with MFS samples when an additional group of unaffected and MFS affected subjects were analyzed (p-value < 3 x 10-6 under the null hypothesis that expression levels in cultured fibroblasts are unaffected by MFS status). An unexpected observation was the range of individual gene expression. In unaffected control subjects, expression ranges exceeding 10 fold were seen in many of the genes selected for qRT-PCR validation. The variation in expression in the MFS affected subjects was even greater. Keywords: disease state comparison; Marfan syndrome; cultured skin fibroblasts
2007-09-14 | GSE8759 | GEO
Project description:Fibroblasts are polymorphic cells with pleiotropic roles in organ morphogenesis, tissue homeostasis and immune responses. In fibrotic diseases, fibroblasts synthesize abundant amounts of extracellular matrix which lead to scaring and organ failure. In sharp contrast, the hallmark feature of fibroblasts in arthritis is matrix degradation by the release of metalloproteinases and degrading enzymes, and subsequent tissue destruction. The mechanisms driving these functionally opposing pro-fibrotic and pro-inflammatory phenotypes of fibroblasts are enigmatic. We have compared resting, fibrotic, and inflammatory fibroblasts; PU.1 was overexpressed in dermal fibroblasts and compared to scr-transfected controls. Fibrotic fibroblasts isolated from the skin of patients with systemic sclerosis were treated with PU.1 inhibitor and compared to untreated fibrotic fibroblasts and respective healthy controls. Through this, we identified the transcription factor PU.1 as an essential orchestrator of the pro-fibrotic gene expression program. The interplay between transcriptional and post-transcriptional mechanisms which normally control PU.1 expression is perturbed in fibrotic diseases such as pulmonary fibrosis, systemic sclerosis, liver cirrhosis, kidney fibrosis and chronic graft-versus-host disease, resulting in upregulation of PU.1, the induction of fibrosis-associated gene sets, and a phenotypic switch in matrix-producing pro-fibrotic fibroblasts. In contrast, inactivation of PU.1 disrupts the fibrotic network and enables re-programming of fibrotic fibroblasts into resting fibroblasts with regression of fibrosis in different organs. Targeting of PU.1 may thus represent a novel therapeutic approach for the treatment of a wide range of fibrotic diseases.
2018-11-09 | GSE122334 | GEO
Project description:Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin-1 (Fbn1) gene. While aortic rupture is the major cause of mortality in MFS, patients also suffer from poorly understood pulmonary complications. Loss of basal nitric oxide (NO) production and vascular integrity are proposed to take part in MFS aortic root disease, yet their contribution to lung complications has yet to be determined. Due to its capacity to potentiate the vasodilatory NO/cyclic guanylate monophosphate signaling pathway, we assessed whether the phosphodiesterase-5 (PDE5) inhibitor sildenafil (SIL) could attenuate aortic root remodelling and emphysema in a mouse model of MFS. Despite increasing NO-dependent vasodilation, SIL unexpectedly elevated mean arterial blood pressure, failed to inhibit MFS aortic root dilation and exacerbated elastic fibrefiber fragmentation. In the lung, early pulmonary artery dilation observed in untreated MFS mice was delayed by SIL treatment, and severe emphysema-like alveolar destruction was prevented. In addition, improvements in select parameters of lung function were documented. Subsequent micro-array analyses showed changes to gene signatures involved in the inflammatory response in MFS lung treated with SIL, without significant downregulation of connective tissue or TGF-β signalling genes. Since PDE5 inhibition leads to improved lung histopathology and function, the effects of SIL against emphysema warrant further investigation in the settings of MFS despite limited efficacy on aortic root remodelling.
2019-03-19 | GSE128481 | GEO