Journal of molecular medicine : official organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
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Antimicrobial peptides possess a myriad of molecular properties including bacterial killing and the regulation of many aspects of innate immunity. Cathelicidins are a group of antimicrobial peptides widely investigated by the scientific community. ⋯ Cathelicidin-deficient mice showed increased survival compared to WT mice in this established experimental model of polymicrobial sepsis, in association with upregulation of certain key inflammatory response genes. Therefore, cathelicidins can exert both pro- and anti-inflammatory activities depending on the disease and cellular context.
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Review
Stem cell-derived organoids and their application for medical research and patient treatment.
3D culture has allowed the initiation and expansion of organ-like structures, called organoids, from either tissue-resident adult stem cells or pluripotent stem cells. Today, organoids can be grown to resemble a wide variety of organs, exhibiting remarkable similarity to their in vivo counterparts. ⋯ They have already found their way into the clinic, enabling personalized medicine in small patient trials. In this review, we provide an update on current organoid technology and summarize their application in basic research, disease modelling, drug development, personalized treatment and regenerative medicine.
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Growing evidence indicates that intracellular signaling mediated by extracellular vesicles (EVs) released by stem cells plays a considerable role in triggering the regenerative program upon transplantation. EVs from umbilical cord mesenchymal stem cells (UC-MSC-EVs) have been shown to enhance tissue repair in animal models. However, translating such results into clinical practice requires optimized EV collection procedures devoid of animal-originating agents. ⋯ Importantly, we found distinct molecular and functional properties of xeno-free UC-MSC-EVs including enhanced cardiomyogenic and angiogenic potential impacting on target cells, which may be explained by elevated concentration of several pro-cardiogenic and pro-angiogenic microRNA (miRNAs) present in the EVs. Our data also suggest predominantly low immunogenic capacity of certain xeno-free UC-MSC-EVs reflected by their inhibitory effect on proliferation of immune cells in vitro. Summarizing, conscious selection of cell culture conditions is required to harvest UC-MSC-EVs with the optimal desired properties including enhanced cardiac and angiogenic capacity, suitable for tissue regeneration.
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Experimental autoimmune myocarditis (EAM) is an inflammatory cardiac disease driven by autoantigen-specific CD4+ T cells. Th17 and Treg cells are crucial participants in immune response. A wide variety of immune disorders are associated with Th17/Treg imbalance. MicroRNA-155 (miR-155) is a pivotal regulator of the immune system. However, the modulatory effect of miR-155 on Th17/Treg immune response during EAM is unknown. Our study aims to investigate the potential role of miR-155 on the development of autoimmune myocarditis. In this study, we revealed that miR-155 expression was highly elevated in heart tissue and CD4+ T cells during EAM. Also, we identified a proliferative and functional imbalance of Th17/Treg in EAM, which is due to a more active development of Th17 cells and an increased resistance of Th17 cells to Treg-mediated suppression. MiR-155 inhibition in EAM resulted in attenuated severity of disease and cardiac injury, reduced Th17 immune response, and decreased dendritic cell (DC) function of secreting Th17-polarizing cytokines. Furthermore, CD4+ T cells from miR-155-inhibited EAM mice exhibited reduced proliferation and IL-17A secretion in response to autoantigen. Finally, we confirmed an indispensable positive role of miR-155 on the differentiation of Th17 cells and the DC function of secreting Th17-polarizing cytokines through in vitro studies. These findings demonstrated that miR-155 adversely promotes EAM by driving a Th17/Treg imbalance in favor of Th17 cells, and anti-miR-155 treatment can significantly reduce the autoimmune response thus to ameliorate EAM, suggesting that miR-155 inhibition could be a promising therapeutic strategy for the treatment of autoimmune myocarditis. ⋯ MiR-155 expression was highly elevated in EAM mice. An imbalance of Th17/Treg existed in EAM mice. MiR-155 inhibition in EAM attenuated disease severity and cardiac injury. MiR-155 inhibition suppressed Th17 immune response in EAM. MiR-155 inhibition reduced DC function of secreting Th17-polarizing cytokines in EAM.
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MicroRNAs (miRNAs) play important roles in the pathogenesis of pulmonary arterial hypertension (PAH). However, the pathways targeted by miRNAs in PAH have not been systematically investigated. We aim to identify dysregulated miRNAs for patients with idiopathic PAH (IPAH). miRNA profiling was performed on lung tissue total RNA from eight IPAH patients and eight control subjects. Real-time quantitative RT-PCR (qRT-PCR) was used for validation of miRNA and mRNA expression levels in 14 IPAH patients and 14 control subjects. Pathway enrichment analysis showed that Wnt/β-catenin signaling is among the top PAH-related pathways enriched in target genes of dysregulated miRNAs. We confirmed the significant increased expression levels of five miRNAs (let-7a-5p, miR-26b-5p, miR-27b-3p, miR-199a-3p and miR-656) targeting major PAH-related pathways. Moreover, qRT-PCR validation of Wnt/β-catenin pathway activation indicated multiple genes including receptors (FZD4, FZD5), core molecule (CTNNB1), and downstream targets (CCND1, VEGFA, and AXIN2) were significantly upregulated. The expression level of miR-199b-5p was positively correlated with patients' hemodynamics (PVR: r = 0.522, p = 0.038) and pulmonary vascular remodeling (muscularization: r = 0.540, p = 0.021). We confirmed overexpression of miR-199b-5p in hypoxic pulmonary arterial endothelial cells that negatively regulates GSK3B expression. In summary, miRNAs influence the pathogenesis of PAH by regulating major PAH-related pathways including Wnt/β-catenin in end-stage IPAH. ⋯ It is the first miRNA profiling study in lung tissue from end-stage idiopathic PAH. We identified dysregulated miRNAs and major pathways (e.g., Wnt signaling) in IPAH. Levels of miRNA expression were correlated with hemodynamics and pathological changes. We observed aberrant expression of target genes in the Wnt/β-catenin pathway. miRNAs influence the pathogenesis of PAH by regulating major PAH-related pathways.