Argininosuccinate synthase (ASS1) is a ubiquitous enzyme in mammals that catalyzes the formation of argininosuccinate from citrulline and aspartate. ASS1 genetic deficiency in patients leads to an ...autosomal recessive urea cycle disorder citrullinemia, while its somatic silence or down-regulation is very common in various human cancers. Here, we show that ASS1 functions as a tumor suppressor in breast cancer, and the pesticide spinosyn A (SPA) and its derivative LM-2I suppress breast tumor cell proliferation and growth by binding to and activating ASS1. The C13-C14 double bond in SPA and LM-2I while the Cys97 (C97) site in ASS1 are critical for the interaction between ASS1 and SPA or LM-2I. SPA and LM-2I treatment results in significant enhancement of ASS1 enzymatic activity in breast cancer cells, particularly in those cancer cells with low ASS1 expression, leading to reduced pyrimidine synthesis and consequently the inhibition of cancer cell proliferation. Thus, our results establish spinosyn A and its derivative LM-2I as potent ASS1 enzymatic activator and tumor inhibitor, which provides a therapeutic avenue for tumors with low ASS1 expression and for those non-tumor diseases caused by down-regulation of ASS1.
Sjögren syndrome (SS) is a systemic autoimmune disease characterized by dry mouth and eyes, and the cellular and molecular mechanisms for its pathogenesis are complex. Here we reveal, for the first ...time, that bone marrow mesenchymal stem cells in SS-like NOD/Ltj mice and human patients were defective in immunoregulatory functions. Importantly, treatment with mesenchymal stem cells (MSCs) suppressed autoimmunity and restored salivary gland secretory function in both mouse models and SS patients. MSC treatment directed T cells toward Treg and Th2, while suppressing Th17 and Tfh responses, and alleviated disease symptoms. Infused MSCs migrated toward the inflammatory regions in a stromal cell–derived factor-1–dependent manner, as neutralization of stromal cell–derived factor-1 ligand CXCR4 abolished the effectiveness of bone marrow mesenchymal stem cell treatment. Collectively, our study suggests that immunologic regulatory functions of MSCs play an important role in SS pathogenesis, and allogeneic MSC treatment may provide a novel, effective, and safe therapy for patients with SS. This study was registered at www.clinicaltrials.gov as NCT00953485.
Aim
The purpose of this study was to investigate the immunomodulatory properties of periodontal ligament stem cells derived from inflamed periodontal ligament tissues.
Material and Methods
...Periodontal ligament stem cells were identified and isolated from healthy or inflamed periodontal ligament tissues. Peripheral blood mononuclear cells were cocultured with inflamed or healthy periodontal ligament stem cells, and T‐lymphocyte proliferation was determined by incubation with carboxyfluorescein succinimidyl ester. T‐helper cells (Th1/Th2, Th17) and regulatory T cells were analysed by flow cytometry. Cytokine profiles in supernatants were tested with a cytometric bead array.
Results
Compared to healthy cells, inflamed periodontal ligament stem cells showed significantly diminished inhibition of T‐cell proliferation. In cocultures, stimulated peripheral blood mononuclear cells showed significantly less induction of CD4+CD25+FOXP3+ regulatory T cells and IL‐10 secretion in the presence of inflamed compared with healthy periodontal ligament stem cells. Furthermore, suppression of Th17 differentiation and IL‐17 production by inflamed periodontal ligament stem cells was significantly lesser than by healthy cells.
Conclusion
This study demonstrated that inflamed periodontal ligament stem cells had markedly dysfunctional immunomodulatory properties; this may contribute to an imbalanced immune response, acceleration of osteoclastogenesis and inflammatory alveolar bone loss in periodontitis.
The osteogenic potential of bone marrow mesenchymal stem cells (BMSCs) declines dramatically with aging. By using a calvarial defect model, we showed that a senolytic cocktail (dasatinib+quercetin; D ...+ Q) improved osteogenic capacity of aged BMSC both in vitro and in vivo. The study presented a model to assess strategies to improve bone-forming potential on aged BMSCs. D + Q might hold promise for improving BMSC function in aged populations.
Fibrosis is a pathological process that affects multiple organs and is considered one of the major causes of morbidity and mortality in multiple diseases, resulting in an enormous disease burden. ...Current studies have focused on fibroblasts and myofibroblasts, which directly lead to imbalance in generation and degradation of extracellular matrix (ECM). In recent years, an increasing number of studies have focused on the role of epithelial cells in fibrosis. In some cases, epithelial cells are first exposed to external physicochemical stimuli that may directly drive collagen accumulation in the mesenchyme. In other cases, the source of stimulation is mainly immune cells and some cytokines, and epithelial cells are similarly altered in the process. In this review, we will focus on the multiple dynamic alterations involved in epithelial cells after injury and during fibrogenesis, discuss the association among them, and summarize some therapies targeting changed epithelial cells. Especially, epithelial mesenchymal transition (EMT) is the key central step, which is closely linked to other biological behaviors. Meanwhile, we think studies on disruption of epithelial barrier, epithelial cell death and altered basal stem cell populations and stemness in fibrosis are not appreciated. We believe that therapies targeted epithelial cells can prevent the progress of fibrosis, but not reverse it. The epithelial cell targeting therapies will provide a wonderful preventive and delaying action.
Display omitted
•The long-neglected epithelial cells are an important mediator of fibrosis.•Epithelial cells offer a new intervention in clinical care for fibrosis.•Targeting epithelial cells can prevent fibrosis progression, but not reverse it.
In the last decade, numerous circRNAs were discovered by virtue of the RNA-Seq technique. With the deepening of experimental research, circRNAs have brought to light the key biological functions and ...progression of human diseases. CircRNA ITCH has been demonstrated to be a tumor suppressor in numerous cancers, and recently it was found to play an important role in bone diseases, diabetes mellitus, and cardiovascular diseases. However, the functions of circ-ITCH have not been completely understood. In this review, we comprehensively provide a conceptual framework to elucidate circ-ITCH biological functions of cell proliferation, apoptosis and differentiation, and the pathological mechanisms of inflammation, drug resistance/toxicity, and tumorigenesis. Finally, we summarize its clinical applications in various diseases. This research aimed at clarifying the role of circ-ITCH, which could be a promising therapeutic target.
Dental pulp stem cell (DPSC)-mediated dental pulp regeneration is considered a promising method for the treatment of deep caries with pulpitis. However, mesenchymal stem cell (MSC) senescence is an ...adverse factor from the perspective of cell-based therapies. In this study, we investigated the characteristics and expression profiles of DPSCs from young and old donors.
DPSCs from young and old donors were cultured in differentiation medium, and their differentiation potentials were assessed. Long noncoding RNA (LncRNA) microarray assays and a bioinformatic analysis were performed to investigate differences in LncRNA and mRNA expression profiles between DPSCs from young and old donors.
We found that DPSCs from young donors exhibited more powerful proliferation ability and greater osteogenic and adipogenic differentiation potentials than DPSCs from old donors. In DPSCs from young donors, numerous LncRNAs were significantly up- (n = 389) or down-regulated (n = 172) compared to DPSCs from old donors. Furthermore, 304 mRNAs were differentially expressed, including 247 up-regulated genes and 57 down-regulated genes in DPSCs from young donors. The bioinformatic analysis identified that several pathways may be associated with DPSC characteristics, such as those involved in the cell cycle and RNA transport, and revealed nuclear transcription factor Y subunit β, general transcription factor IIB, and nuclear receptor subfamily 3 group C member 1 as core regulatory factors and FR249114, FR299091, and ENST00000450004 as core LncRNAs.
Our results indicated that senescence impaired the proliferation and differentiation potentials of DPSCs and that donor age is an important factor that affects their use for tooth regeneration. We also provide insight into the mechanisms responsible for senescence in DPSCs.
Modeling and remodeling are essential processes in the development and refinement of maxillofacial bones. Dysregulated bone modeling during the developmental stage may lead to maxillofacial bone ...malformations and malocclusion. Bone remodeling under mechanical loading serves as the biological basis for orthodontic treatment. Although previous reviews have indicated the significance of microRNAs (miRNAs) in bone metabolism, their roles in orchestrating maxillofacial bone modeling and remodeling remain unclear. This review aims to discuss the mechanisms by which miRNAs regulate the morphogenesis and development of maxillofacial bones, as well as their implications for maxillofacial malformations and malocclusion. Moreover, miRNAs participating in maxillofacial bone remodeling and their impacts on cell mechanosensing are also summarized. Given the intricate interplay of cells and signaling pathways, exosomal miRNAs emerge as the orchestrators of the modeling and remodeling processes. The diagnostic and therapeutic potentials of miRNAs are also highlighted in this review for future clinical applications.
Periodontal ligament stem cells (PDLSCs) have provided novel cell sources for tooth and periodontal tissue regeneration. Allogeneic PDLSCs can reconstruct periodontal ligament tissue that has been ...damaged by periodontal diseases and regulate T‐cell immunity. However, the effect of PDLSCs on B cells remains unknown. Here, we treated periodontitis in a miniature pig model using allogeneic PDLSCs and showed a reduction in humoral immunity in the animals. When cocultured with normal B cells, human PDLSCs (hPDLSCs) had similar effects as bone marrow mesenchymal stem cells in suppressing B cell proliferation, differentiation, and migration, while intriguingly, hPDLSCs increased B cell viability by secreting interleukin‐6. Mechanistically, hPDLSCs suppressed B cell activation through cell‐to‐cell contact mostly mediated by programmed cell death protein 1 and programmed cell death 1 ligand 1. Our data revealed a previously unrecognized function of PDLSCs in regulating humoral immune responses, which may represent a novel therapeutic strategy for immune‐related disorders. STEM Cells2013;31:1371–1382
Interleukin (IL)‐33, a member of the IL‐1 superfamily, functions as an alarm signal, which is released upon cell injury or tissue damage to alert the immune system. It has emerged as a chief ...orchestrator in immunity and has a broad pleiotropic action that influences differentiation, maintenance and function of various immune cell types via the ST2 receptor. Although it has been strongly associated with immunopathology, critically, IL‐33 is involved in host defence, tissue repair and homeostasis. In this review, we provide an overview of the signalling pathway of IL‐33 and highlight its regulatory functions in immune cells. Furthermore, we attempt a broader discussion of the emerging functions of IL‐33 in host defence, tissue repair, metabolism, inflammatory disease and cancer, suggesting potential avenues to manoeuvre IL‐33/ST2 signalling as treatment options.
In this article, we summarise the current understanding of IL‐33 and its effect on immune cells and focus on the functions of IL‐33 in host defence and inflammation. In particular, we highlight their less well‐appreciated roles in tissue repair and homeostasis.
PDF
