Mechanistic Study of a Preconditioned Silicotic Inflammatory Microenvironment Combined with Bone Marrow Mesenchymal Stem Cell Therapy for Silicosis Fibrosis
Ontology highlight
ABSTRACT:
ORGANISM(S): Rattus Norvegicus 挪威鼠
SUBMITTER: 
Zhongjun Du
PROVIDER: PXD053446 | iProX | Thu Jun 27 00:00:00 BST 2024
REPOSITORIES: iProX
Similar Datasets
Project description:MSC senescence is considered a contributing factor in aging-related diseases. We investigated the influence of the inflammatory microenvironment on bone marrow mesenchymal stem cells (BMSCs) under aging conditions and the underlying mechanism to provide new ideas for stem cell therapy for age-related osteoporosis. The BMSCs were cultured until passage 3 (P3) (young group) and passage 10 (P10) (aging group) in vitro. The supernatant was collected as the conditioned medium (CM). The young BMSCs were cultured in the CM of P3 or P10 cells. The effects of CM from different groups on the aging and stemness of the young BMSCs were examined. A Quantibody® mouse inflammation array on serum extracts from young (aged 8 weeks) and old (aged 78 weeks) mice was performed, and differentially expressed factors were screened out. We discovered that the CM from senescent MSCs changed the physiology of young BMSCs. Systemic inflammatory microenvironments changed with age in the mice. In particular, the pro-inflammatory cytokine IL-6 increased, and the anti-inflammatory cytokine IL-10 decreased. The underlying mechanism was investigated by GO and KEGG analyses, and there was a change in the JAK-STAT signaling pathway, which is closely related to IL-6 and IL-10. Collectively, our results demonstrated that the age-related inflammatory microenvironment has a significant effect on the biological functions of BMSCs. Targeted reversal of this inflammatory environment may provide a new strategy for stem cell therapy to treat aging-related skeletal diseases.
| S-EPMC9133389 | biostudies-literature
Project description:Bone marrow (BM)-derived mesenchymal stromal cells (MSCs) are promising candidates for cell-based therapy for several immune-mediated inflammatory diseases (IMIDs) due to their multiplicity of immunomodulatory and reparative properties and favorable safety profile. However, although preclinical data were encouraging, the clinical benefit demonstrated in clinical trials of autologous MSC transplantation in a number of conditions has been less robust. This may be explained by the growing body of evidence pointing to abnormalities of the bone marrow microenvironment in IMIDs, including impaired MSC function. However, it is not currently known whether these abnormalities arise as a cause or consequence of disease, the role they play in disease initiation and/or progression, or whether they themselves are targets for disease modification. Here, we review current knowledge about the function of the BM microenvironment in IMIDs including multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, and type I diabetes, focusing on MSCs in particular. We predict that an improved understanding of disease-related changes in the bone marrow microenvironment including the role of MSCs in vivo, will yield new insights into pathophysiology and aid identification of new drug targets and optimization of cell-based therapy in IMIDs.
| S-EPMC10940816 | biostudies-literature
Project description:B lymphopoiesis arrests precipitously in rabbits such that by 2-4 mo of age, before sexual maturity, little to no B lymphopoiesis occurs in the bone marrow (BM). Previously, we showed that in mice, adipocytes inhibit B lymphopoiesis in vitro by inducing inflammatory myeloid cells, which produce IL-1β. In this study, we characterized rabbit BM after the arrest of B lymphopoiesis and found a dramatic increase in fat, increased CD11b+ myeloid cells, and upregulated expression of the inflammatory molecules, IL-1β and S100A9, by the myeloid cells. We added BM fat, CD11b+ myeloid cells, and recombinant S100A9 to B lymphopoiesis cultures and found that they inhibited B lymphopoiesis and enhanced myelopoiesis. Unlike IL-1β, which inhibits B lymphopoiesis by acting on early lymphoid progenitors, S100A9 inhibits B lymphopoiesis by acting on myeloid cells and promoting the release of inflammatory molecules, including IL-1β. Many molecules produced by adipocytes activate the NLRP3 inflammasome, and the NLRP3 inhibitor, glibenclamide, restored B lymphopoiesis and minimized induction of myeloid cells induced by adipocyte-conditioned medium in vitro. We suggest that fat provides an inflammatory microenvironment in the BM and promotes/activates myeloid cells to produce inflammatory molecules such as IL-1β and S100A9, which negatively regulate B lymphopoiesis.
| S-EPMC5435233 | biostudies-literature
Project description:The bone marrow constitutes an unique microenvironment for cancer cells in three specific aspects. First, the bone marrow actively recruits circulating tumor cells where they find a sanctuary rich in growth factors and cytokines that promote their proliferation and survival. When in the bone marrow, tumor cells profoundly affect the homeostasis of the bone and the balance between osteogenesis and osteolysis. As a consequence, growth and survival factors normally sequestered into the bone matrix are released, further fueling cancer progression. Second, tumor cells actively recruit bone marrow-derived precursor cells into their own microenvironment. When in the tumors, these bone marrow-derived cells contribute to an inflammatory reaction and to the formation of the tumor vasculature. Third, bone marrow-derived cells can home in distant organs, where they form niches that attract circulating tumor cells. Our understanding of the contribution of the bone marrow microenvironment to cancer progression has therefore dramatically improved over the last few years. The importance of this new knowledge cannot be underestimated considering that the vast majority of cancer treatments such as cytotoxic and myeloablative chemotherapy, bone marrow transplantation and radiation therapy inflict a trauma to the bone marrow microenvironment. How such trauma affects the influence that the bone marrow microenvironment exerts on cancer is still poorly understood. In this article, the reciprocal relationship between the bone marrow microenvironment and tumor cells is reviewed, and its potential impact on cancer therapy is discussed.
| S-EPMC2654350 | biostudies-other
Project description:Anemia is characteristic of myelodysplastic syndromes (MDS). The mechanisms of anemia in MDS are unclear. Using a mouse genetic approach, here we show that dual deficiency of mDia1 and miR-146a, encoded on chromosome 5q and commonly deleted in MDS (del(5q) MDS), causes an age-related anemia and ineffective erythropoiesis mimicking human MDS. We demonstrate that the ageing bone marrow microenvironment is important for the development of ineffective erythropoiesis in these mice. Damage-associated molecular pattern molecules (DAMPs), whose levels increase in ageing bone marrow, induced TNFα and IL-6 upregulation in myeloid-derived suppressor cells (MDSCs) in mDia1/miR-146a double knockout mice. Mechanistically, we reveal that pathologic levels of TNFα and IL-6 inhibit erythroid colony formation and differentially affect terminal erythropoiesis through reactive oxygen species-induced caspase-3 activation and apoptosis. Treatment of the mDia1/miR-146a double knockout mice with all-trans retinoic acid, which promoted the differentiation of MDSCs and ameliorated the inflammatory bone marrow microenvironment, significantly rescued anemia and ineffective erythropoiesis. Our study underscores the dual roles of the ageing microenvironment and genetic abnormalities in the pathogenesis of ineffective erythropoiesis in del(5q) MDS.
| S-EPMC5886057 | biostudies-literature
Project description:Background and objectivesChronic inflammation of bone tissue often results in bone defects and hazards to tissue repair and regeneration. Cannabidiol (CBD) is a natural cannabinoid with multiple biological activities, including anti-inflammatory and osteogenic potential. This study aimed to investigate the efficacy and mechanisms of CBD in the promotion of bone marrow mesenchymal stem cells (BMSCs) osteogenic differentiation in the inflammatory microenvironment.Methods and resultsBMSCs isolated from C57BL/6 mice, expressed stem cell characteristic surface markers and presented multidirectional differentiation potential. The CCK-8 assay was applied to evaluate the effects of CBD on BMSCs' vitality, and demonstrating the safety of CBD on BMSCs. Then, BMSCs were stimulated with lipopolysaccharide (LPS) to induce inflammatory microenvironment. We found that CBD intervention down-regulated mRNA expression levels of inflammatory cytokines and promoted cells proliferation in LPS-treated BMSCs, also reversed the protein and mRNA levels downregulation of osteogenic markers caused by LPS treatment. Moreover, CBD intervention activated the cannabinoid receptor 2 (CB2) and the p38 mitogen-activated protein kinase (MAPK) signaling pathway. While AM630, a selective CB2 inhibitor, reduced phosphorylated (p)-p38 levels. In addition, AM630 and SB530689, a selective p38 MAPK inhibitor, attenuated the enhancement of osteogenic markers expression levels by CBD in inflammatory microenvironment, respectively.ConclusionsCBD promoted osteogenic differentiation of BMSCs via the CB2/p38 MAPK signaling pathway in the inflammatory microenvironment.
| S-EPMC9705154 | biostudies-literature
Project description:Bone regeneration is driven by mesenchymal stromal cells (MSCs) via their interactions with immune cells, such as macrophages (MPs). Bone substitutes, e.g., bi-calcium phosphates (BCPs), are commonly used to treat bone defects. However, little research has focused on MSC responses to BCPs in the context of inflammation. The objective of this study was to investigate whether BCPs influence MSC responses and MSC-MP interactions, at the gene and protein levels, in an inflammatory microenvironment. In setup A, human bone marrow MSCs combined with two different BCP granules (BCP 60/40 or BCP 20/80) were cultured with or without cytokine stimulation (IL1β + TNFα) to mimic acute inflammation. In setup B, U937 cell-line-derived MPs were introduced via transwell cocultures to setup A. Monolayer MSCs with and without cytokine stimulation served as controls. After 72 h, the expressions of genes related to osteogenesis, healing, inflammation and remodeling were assessed in the MSCs via quantitative polymerase chain reactions. Additionally, MSC-secreted cytokines related to healing, inflammation and chemotaxis were assessed via multiplex immunoassays. Overall, the results indicate that, under both inflammatory and non-inflammatory conditions, the BCP granules significantly regulated the MSC gene expressions towards a pro-healing genotype but had relatively little effect on the MSC secretory profiles. In the presence of the MPs (coculture), the BCPs positively regulated both the gene expression and cytokine secretion of the MSCs. Overall, similar trends in MSC responses were observed with BCP 60/40 and BCP 20/80. In summary, within the limits of in vitro models, these findings suggest that the presence of BCP granules at a surgical site may not necessarily have a detrimental effect on MSC-mediated wound healing, even in the event of inflammation.
| S-EPMC9820717 | biostudies-literature
Project description:Philadelphia-negative myeloproliferative neoplasms (MPN) are malignant bone marrow (BM) disorders, typically arising from a single somatically mutated hematopoietic stem cell. The most commonly mutated genes, JAK2, CALR, and MPL lead to constitutively active JAK-STAT signaling. Common clinical features include myeloproliferation, splenomegaly and constitutional symptoms. This review covers the contributions of cellular components of MPN pathology (e.g., monocytes, megakaryocytes, and mesenchymal stromal cells) as well as cytokines and soluble mediators to the development of myelofibrosis (MF) and highlights recent therapeutic advances. These findings outline the importance of malignant and non-malignant BM constituents to the pathogenesis and treatment of MF.
| S-EPMC7489333 | biostudies-literature
Project description:Bone marrow mesenchymal stromal cells (BM-MSCs) have anti-inflammatory and pro-survival properties. Naturally, they do not express human leukocyte antigen class II surface antigens and have immunosuppressive capabilities. Together with their relatively easy accessibility and expansion, they are an attractive tool for organ support in transplantation and regenerative therapy. Autologous BM-MSC transplantation alone or together with transplanted islets improves β-cell function, graft survival, and glycemic control in diabetes. Albeit MSCs' capacity to transdifferentiate into β-cell is limited, their protective effects are mediated mainly by paracrine mechanisms through BM-MSCs circulating through the body. Direct cell-cell contact and spontaneous fusion of BM-MSCs with injured cells, although at a very low rate, are further mechanisms of their supportive effect and for tissue regeneration. Diabetes is a disease of long-term chronic inflammation and cell therapy requires stable, highly functional cells. Several tools and protocols have been developed by mimicking natural fusion events to induce and accelerate fusion in vitro to promote β-cell-specific gene expression in fused cells. BM-MSC-islet fusion before transplantation may be a strategy for long-term islet survival and improved function. This review discusses the cell-protective and anti-inflammatory characteristics of BM-MSCs to boost highly functional insulin-producing cells in vitro and in vivo, and the efficacy of their fusion with β-cells as a path to promote β-cell regeneration.
| S-EPMC9327419 | biostudies-literature
Project description:Anti-inflammatory effects of bone marrow mesenchymal stem cells (BMSCs) on mice with Alzheimer's disease (AD) were investigated. Twenty amyloid precursor protein (APP)/presenilin-1 (PS1) double transgenic mice were randomly divided into two groups: the AD control group and the stem cell treatment group. The normal control group consisted of 10 non-transgenic mice. The stem cell treatment group was injected with BMSCs, and the two control groups were given the same volume of normal saline. The Morris water maze test was used to compare the memory function of mice, and the relative expression levels of ?-site APP cleaving enzyme 1 (BACE1) and ?-2-macroglobulin (A2M) genes were detected by fluorescence quantitative polymerase chain reaction (qPCR). Amyloid ? (A?)1-42 content in brain tissues of mice and inflammatory cytokines, interleukin (IL)-1, IL-2, IL-10, tumor necrosis factor-? (TNF-?), and interferon-? (IFN-?) were detected using enzyme-linked immunosorbent assay (ELISA). Compared with that in the AD control group, the escape latency in the water maze in the stem cell treatment group was shortened, the time of crossing the ring for the first time was decreased, but the frequency of crossing the ring was increased (P<0.05). A?1-42 content in the AD control group was higher than that in the stem cell treatment group and the normal control group (P<0.05). The relative expression level of BACE1 gene in the stem cell treatment group was lower than that in the AD control group (P<0.05), but that of A2M gene was increased (P<0.05). At 14 days after treatment, the contents of IL-1, IL-2, TNF-? and IFN-? in blood in the stem cell treatment group were lower than those in the AD control group (P<0.05). Human BMSCs can ameliorate the symptoms of AD by decreasing the levels of inflammatory cytokines and regulating the expression of A?-related genes.
| S-EPMC6257159 | biostudies-other