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International Immunopharmacology Oct 2023Tracheal injury is a challenging emergency condition that is characterized by the abnormal repair of the trachea. GATA6, a well-established transcription factor, plays a...
Tracheal injury is a challenging emergency condition that is characterized by the abnormal repair of the trachea. GATA6, a well-established transcription factor, plays a crucial role in tissue injury and epithelial regenerative repair. This study aims to evaluate the role of GATA6 in NF-κB-mediated NLRP3 inflammasome activation and pyroptosis after tracheal injury. Tracheal tissues and serum samples were collected from clinical patients and a rat model of tracheal injury. Upon GATA6 knockdown or overexpression, BEAS-2B and rat tracheal epithelial (RTE) cells were treated with lipopolysaccharides and nigericin before being co-cultured with primary tracheal fibroblasts. The changes of NLRP3 inflammasome activation and pyroptosis and their underlying mechanisms were detected. Additionally, the role of GATA6 downregulation in tracheal injury was verified in rats. GATA6 expression and NLRP3 inflammasome activation were upregulated following tracheal injury in the epithelium of granulation tissues. GATA6 silencing inhibited NLRP3 priming, NLRP3 inflammasome activation, and pyroptosis in BEAS-2B and RTE cells. Mechanistically, GATA6 was determined to have bound to the promoter region of NLRP3 and synergistically upregulated NLRP3 promoter activity with NF-κB. Furthermore, GATA6 overexpression promoted epithelial-mesenchymal transition via modulating the NF-κB/NLRP3 pathway. Epithelial NLRP3 inflammasome activation triggered ECM production in fibroblasts, which was suppressed by GATA6 knockdown and induced by GATA6 overexpression. Finally, the downregulation of GATA6 alleviated NLRP3 inflammasome-mediated pyroptosis induced by tracheal injury in rats, thereby reducing tracheal stenosis, inflammation, and fibrosis. GATA6 promotes fibrotic repair in tracheal injury through NLRP3 inflammasome-mediated epithelial pyroptosis, making it a potential biological therapeutic target for tracheal injury.
Topics: Animals; Humans; Rats; Fibrosis; GATA6 Transcription Factor; Inflammasomes; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis; Trachea
PubMed: 37531826
DOI: 10.1016/j.intimp.2023.110657 -
Stem Cells and Development Jan 2024The health of hair is directly related to people's health and appearance. Hair has key physiological functions, including skin protection and temperature regulation.... (Review)
Review
The health of hair is directly related to people's health and appearance. Hair has key physiological functions, including skin protection and temperature regulation. Hair follicle (HF) is a vital mini-organ that directly impacts hair growth. Besides, various signaling pathways and molecules regulate the growth cycle transition of HFs. Hair and its regeneration studies have attracted much interest in recent years with the increasing rate of alopecia. Mesenchymal stem cells (MSCs), as pluripotent stem cells, can differentiate into fat, bone, and cartilage and stimulate regeneration and immunological regulation. MSCs have been widely employed to treat various clinical diseases, such as bone and cartilage injury, nerve injury, and lung injury. Besides, MSCs can be used for treatment of hair diseases due to their regenerative and immunomodulatory abilities. This review aimed to assess MSCs' treatment for alopecia, pertinent signaling pathways, and new material for hair regeneration in the last 5 years.
Topics: Humans; Hair; Hair Follicle; Alopecia; Mesenchymal Stem Cells; Signal Transduction
PubMed: 37847179
DOI: 10.1089/scd.2023.0156 -
Journal of Cardiovascular Development... Oct 2023The embryonic epicardium originates from the proepicardium, an extracardiac primordium constituted by a cluster of mesothelial cells. In early embryos, the embryonic... (Review)
Review
The embryonic epicardium originates from the proepicardium, an extracardiac primordium constituted by a cluster of mesothelial cells. In early embryos, the embryonic epicardium is characterized by a squamous cell epithelium resting on the myocardium surface. Subsequently, it invades the subepicardial space and thereafter the embryonic myocardium by means of an epithelial-mesenchymal transition. Within the myocardium, epicardial-derived cells present multilineage potential, later differentiating into smooth muscle cells and contributing both to coronary vasculature and cardiac fibroblasts in the mature heart. Over the last decades, we have progressively increased our understanding of those cellular and molecular mechanisms driving proepicardial/embryonic epicardium formation. This study provides a state-of-the-art review of the transcriptional and emerging post-transcriptional mechanisms involved in the formation and differentiation of the embryonic epicardium.
PubMed: 37998498
DOI: 10.3390/jcdd10110440 -
Proceedings of the National Academy of... Aug 2023Ly6C monocytes are a myeloid subset that specializes in the surveillance of vascular endothelium. Ly6C monocytes have been shown to derive from Ly6C monocytes. NOTCH2...
Ly6C monocytes are a myeloid subset that specializes in the surveillance of vascular endothelium. Ly6C monocytes have been shown to derive from Ly6C monocytes. NOTCH2 signaling has been implicated as a trigger for Ly6C monocyte development, but the basis for this effect is unclear. Here, we examined the impact of NOTCH2 signaling of myeloid progenitors on the development of Ly6C monocytes in vitro. NOTCH2 signaling induced by delta-like ligand 1 (DLL1) efficiently induced the transition of Ly6C TREML4 monocytes into Ly6C TREML4 monocytes. We further identified two additional transcriptional requirements for development of Ly6C monocytes. Deletion of BCL6 from myeloid progenitors abrogated development of Ly6C monocytes. IRF2 was also required for Ly6C monocyte development in a cell-intrinsic manner. DLL1-induced in vitro transition into Ly6C TREML4 monocytes required IRF2 but unexpectedly could occur in the absence of NUR77 or BCL6. These results imply a transcriptional hierarchy for these factors in controlling Ly6C monocyte development.
Topics: Monocytes; Endothelium, Vascular; Hematopoiesis; Signal Transduction
PubMed: 37607223
DOI: 10.1073/pnas.2220853120 -
Allergy, Asthma & Immunology Research Sep 2023Although estrogen receptors (ERs) signal pathways are involved in the pathogenesis and development of asthma, their expressions and effects remain controversial. This...
PURPOSE
Although estrogen receptors (ERs) signal pathways are involved in the pathogenesis and development of asthma, their expressions and effects remain controversial. This study aimed to investigate the expressions of ERα and ERβ as well as their mechanisms in airway remodeling and mucus production in asthma.
METHODS
The expressions of ERα and ERβ in the airway epithelial cells of bronchial biopsies and induced sputum cells were examined by immunohistochemistry. The associations of ERs expressions with airway inflammation and remodeling were evaluated in asthmatic patients. , the regulations of ERs expressions in human bronchial epithelial cell lines were examined using western blot analysis. The epidermal growth factor (EGF)-mediated ligand-independent activation of ERα and its effect on epithelial-mesenchymal transitions (EMTs) were investigated in asthmatic epithelial cells by western blot, immunofluorescent staining, and quantitative real-time polymerase chain reaction.
RESULTS
ERα and ERβ were expressed on both bronchial epithelial cells and induced sputum cells, and the expressions showed no sex difference. Compared to controls, male asthmatic patients had higher levels of ERα on the bronchial epithelium, and there were cell-specific expressions of ERα and ERβ in induced sputum. The expression of ERα in the airway epithelium was inversely correlated to forced expiratory volume in 1 second (FEV1) % and FEV1/forced vital capacity. Severe asthmatic patients had significantly greater levels of ERα in the airway epithelium than mild-moderate patients. ERα level was positively correlated with the thickness of the subepithelial basement membrane and airway epithelium. , co-stimulation of interleukin (IL)-4 and EGF increased the expression of ERα and promoted its nuclear translocation. EGF activated the phosphorylation of ERα via extracellular signal-regulated kinase and c-Jun N-terminal kinase pathways. ERα knockdown alleviated EGF-mediated EMTs and mucus production in airway epithelial cells of asthma.
CONCLUSIONS
ERα contributes to asthmatic airway remodeling and mucus production through the EGF-mediated ligand-independent pathway.
PubMed: 37153982
DOI: 10.4168/aair.2023.15.5.614 -
Frontiers in Bioscience (Landmark... Jul 2023N6-methyladenosine (m6A) participates in diverse physiological processes and contributes to many pathological conditions. Epithelial-mesenchymal transition (EMT) of...
BACKGROUND
N6-methyladenosine (m6A) participates in diverse physiological processes and contributes to many pathological conditions. Epithelial-mesenchymal transition (EMT) of retinal pigmental epithelial (RPE) cells plays an essential role in retinal-related diseases, and transforming growth factor β2 (TGF-β2) is known to induce EMT . However, the effect of TGF-β2 on m6A methylation in RPE cells is not yet known.
METHODS
RNA-seq and MeRIP-seq were performed to analyze changes at the mRNA and m6A levels after TGF-β2 treatment of human ARPE-19 cells. mRNA levels and total m6A levels were subsequently validated.
RESULTS
Sequencing revealed 929 differentially expressed genes and 7328 differentially methylated genes after TGF-β2 treatment. Conjoint analysis identified 290 genes related to microtubule cytoskeleton, focal adhesion, ECM-receptor interaction, cell division, cell cycle, AGE-RAGE, PI3K-Akt and cGMP-PKG pathways. Further analysis revealed that 12 EMT-related genes were altered at the mRNA and m6A levels after TGF-β2 treatment (, , , , , , , , , , and ). Moreover, the total m6A level was also reduced.
CONCLUSIONS
This study revealed the transcriptional profiling of m6A modification induced by TGF-β2 in RPE cells. Novel connections were discovered between m6A modification and TGF-β2-induced EMT, suggesting that m6A may play crucial roles in the EMT process.
Topics: Humans; Epithelial-Mesenchymal Transition; Transforming Growth Factor beta2; Retinal Pigment Epithelium; Cell Line; RNA-Seq; Methylation; Adenosine
PubMed: 37525909
DOI: 10.31083/j.fbl2807148 -
JCI Insight Jan 2024Benign prostatic hyperplasia (BPH) is the nodular proliferation of the prostate transition zone in older men, leading to urinary storage and voiding problems that can be...
Benign prostatic hyperplasia (BPH) is the nodular proliferation of the prostate transition zone in older men, leading to urinary storage and voiding problems that can be recalcitrant to therapy. Decades ago, John McNeal proposed that BPH originates with the "reawakening" of embryonic inductive activity by adult prostate stroma, which spurs new ductal proliferation and branching morphogenesis. Here, by laser microdissection and transcriptional profiling of the BPH stroma adjacent to hyperplastic branching ducts, we identified secreted factors likely mediating stromal induction of prostate glandular epithelium and coinciding processes. The top stromal factors were insulin-like growth factor 1 (IGF1) and CXC chemokine ligand 13 (CXCL13), which we verified by RNA in situ hybridization to be coexpressed in BPH fibroblasts, along with their cognate receptors (IGF1R and CXCR5) on adjacent epithelium. In contrast, IGF1 but not CXCL13 was expressed in human embryonic prostate stroma. Finally, we demonstrated that IGF1 is necessary for the generation of BPH-1 cell spheroids and patient-derived BPH cell organoids in 3D culture. Our findings partially support historic speculations on the etiology of BPH and provide what we believe to be new molecular targets for rational therapies directed against the underlying processes driving BPH.
Topics: Male; Adult; Humans; Aged; Prostatic Hyperplasia; Prostate; Epithelium; Fibroblasts; Gene Expression Profiling
PubMed: 37971878
DOI: 10.1172/jci.insight.176479 -
Proceedings of the National Academy of... Aug 2023The auditory organ of Corti is comprised of only two major cell types-the mechanosensory hair cells and their associated supporting cells-both specified from a single...
The auditory organ of Corti is comprised of only two major cell types-the mechanosensory hair cells and their associated supporting cells-both specified from a single pool of prosensory progenitors in the cochlear duct. Here, we show that competence to respond to Atoh1, a transcriptional master regulator necessary and sufficient for induction of mechanosensory hair cells, is established in the prosensory progenitors between E12.0 and 13.5. The transition to the competent state is rapid and is associated with extensive remodeling of the epigenetic landscape controlled by the SoxC group of transcription factors. Conditional loss of and -the two homologous family members transiently expressed in the inner ear at the time of competence establishment-blocks the ability of prosensory progenitors to differentiate as hair cells. Mechanistically, we show that Sox4 binds to and establishes accessibility of early sensory lineage-specific regulatory elements, including ones associated with Atoh1 and its direct downstream targets. Consistent with these observations, overexpression of or prior to developmental establishment of competence precociously induces hair cell differentiation in the cochlear progenitors. Further, reintroducing or expression restores the ability of postnatal supporting cells to differentiate as hair cells in vitro and in vivo. Our findings demonstrate the pivotal role of family members as agents of epigenetic and transcriptional changes necessary for establishing competence for sensory receptor differentiation in the inner ear.
Topics: Animals; SOXC Transcription Factors; Basic Helix-Loop-Helix Transcription Factors; Cochlea; Hair Cells, Auditory; Cell Differentiation; Transcription Factors; Epigenesis, Genetic; Organ of Corti; Gene Expression Regulation, Developmental; Mammals
PubMed: 37585469
DOI: 10.1073/pnas.2301301120 -
Biomolecules & Therapeutics Sep 2023Idiopathic pulmonary fibrosis (IPF) can be defined as a progressive chronic pulmonary disease showing scarring in the lung parenchyma, thereby resulting in increase in... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) can be defined as a progressive chronic pulmonary disease showing scarring in the lung parenchyma, thereby resulting in increase in mortality and decrease in the quality of life. The pathophysiologic mechanism of fibrosis in IPF is still unclear. Repetitive microinjuries to alveolar epithelium with genetical predisposition and an abnormal restorative reaction accompanied by excessive deposition of collagens are involved in the pathogenesis. Although the two FDA-approved drugs, pirfenidone and nintedanib, are under use for retarding the decline in lung function of patients suffered from IPF, they are not able to improve the survival rate or quality of life. Therefore, a novel therapeutic agent acting on the major steps of the pathogenesis of disease and/or, at least, managing the clinical symptoms of IPF should be developed for the effective regulation of this incurable disease. In the present review, we tried to find a potential of managing the clinical symptoms of IPF by natural products derived from medicinal plants used for controlling the pulmonary inflammatory diseases in traditional Asian medicine. A multitude of natural products have been reported to exert an antifibrotic effect and through acting on the epithelial-mesenchymal transition pathway, transforming growth factor (TGF)-β-induced intracellular signaling, and the deposition of extracellular matrix. However, clinical antifibrotic efficacy of these natural products on IPF have not been elucidated yet. Thus, those effects should be proven by further examinations including the randomized clinical trials, in order to develop the ideal and optimal candidate for the therapeutics of IPF.
PubMed: 37254717
DOI: 10.4062/biomolther.2023.056 -
Cardiovascular Diabetology Nov 2023Diabetic cardiomyopathy (DCM) is a major complication of diabetes and a risk factor for cardiovascular disease. Endothelial dysfunction is central to DCM, and...
AIMS
Diabetic cardiomyopathy (DCM) is a major complication of diabetes and a risk factor for cardiovascular disease. Endothelial dysfunction is central to DCM, and endothelial-to-mesenchymal transition (EndMT) is a key form of endothelial dysfunction in diabetes. EndMT in DCM has been well-studied in model systems and has been found to be epigenetically regulated by non-coding RNAs (ncRNAs). However, EndMT in DCM and its associated epigenetic changes need further characterization in human patients. It is also not known if ncRNAs are affected by changes in DNA methylation in DCM. This study aims to confirm in human hearts, the findings from animal and cell studies, and potentially provide novel insight into interactions between DNA methylation and ncRNAs in EndMT in DCM.
METHODS AND RESULTS
Heart tissues were collected from autopsy patients, fixed in formalin, and embedded in paraffin. Thin sections from paraffin-embedded tissues were used for histology and immunofluorescence analyses, where we confirmed that diabetic patients showed increased cardiac fibrosis that EndMT had occurred. Tissue curls from the paraffin-embedded tissues were used for RT-qPCR and methylation analyses. RT-qPCR quantitatively showed that EndMT occurs in the hearts of diabetics, and that EndMT in human hearts corresponded to changes in key ncRNAs. Methylation analysis showed that some of the EndMT-related ncRNAs were regulated by DNA promoter methylation, while others may be regulated through different epigenetic mechanisms.
CONCLUSIONS
We show that EndMT is a relevant pathological process in human hearts during DCM, and that its occurrence coincides with changes in relevant ncRNAs. We further find that interplay between DNA methylation and certain ncRNAs involved in the regulation of EndMT may contribute to the observed changes in ncRNA expression. These findings reinforce the role of EndMT in patients afflicted with DCM and underscore the complexities and importance of the interactions between different facets of epigenetic regulation.
Topics: Animals; Humans; DNA Methylation; Diabetic Cardiomyopathies; Epigenesis, Genetic; Endothelium; RNA, Untranslated; Epithelial-Mesenchymal Transition; Diabetes Mellitus
PubMed: 37924123
DOI: 10.1186/s12933-023-02039-4