Correction: Splenocytes Seed Bone Marrow of Myeloablated Mice: Implication for Atherosclerosis.
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ABSTRACT:
SUBMITTER: PLOS ONE Staff
PROVIDER: S-EPMC4556566 | biostudies-literature | 2015
REPOSITORIES: biostudies-literature
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Correction: Splenocytes Seed Bone Marrow of Myeloablated Mice: Implication for Atherosclerosis.
PloS one 20150901 9
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Project description:Extramedullary hematopoiesis has been shown to contribute to the pathogenesis of a variety of diseases including cardiovascular diseases. In this process, the spleen is seeded with mobilized bone marrow cells that augment its hematopoietic ability. It is unclear whether these immigrant cells that are produced/reprogrammed in spleen are similar or different from those found in the bone marrow. To begin to understand this, we investigated the relative potency of adult splenocytes per se to repopulate bone marrow of lethally-irradiated mice and its functional consequences in atherosclerosis. The splenocytes were harvested from GFP donor mice and transplanted into myeloablated wild type recipient mice without the inclusion of any bone marrow helper cells. We found that adult splenocytes repopulated bone marrow of myeloablated mice and the transplanted cells differentiated into a full repertoire of myeloid cell lineages. The level of monocytes/macrophages in the bone marrow of recipient mice was dependent on the cell origin, i.e., the donor splenocytes gave rise to significantly more monocytes/macrophages than the donor bone marrow cells. This occurred despite a significantly lower number of hematopoietic stem cells being present in the donor splenocytes when compared with donor bone marrow cells. Atherosclerosis studies revealed that donor splenocytes displayed a similar level of atherogenic and atheroprotective activities to those of donor bone marrow cells. Cell culture studies showed that the phenotype of macrophages derived from spleen is different from those of bone marrow. Together, these results demonstrate that splenocytes can seed bone marrow of myeloablated mice and modulate atherosclerosis. In addition, our study shows the potential of splenocytes for therapeutic interventions in inflammatory disease.
| S-EPMC4454495 | biostudies-literature
Project description:Rho kinases (ROCKs) are serine-threonine protein kinases that regulate the actin cytoskeleton. Recent studies suggest that ROCKs also play an important role in cardiovascular disease. However, the isoform- and tissue-specific role of ROCKs in mediating this process is unknown. Using homologous recombination, we generated mutant mice harboring alleles with homozygous deletion of ROCK1 (ROCK1(-/-)). Most ROCK1(-/-) mice die perinatally. However, a few ROCK1(-/-) mice survive to adulthood, are phenotypically normal, and have no apparent compensatory changes in ROCK2. Using these ROCK1(-/-) mice, we show that ROCK1 in bone marrow-derived macrophages is critical to the development of atherosclerosis, in part, by mediating foam cell formation and macrophage chemotaxis. Lipid accumulation and atherosclerotic lesions were reduced in atherosclerosis-prone LDLR(-/-) mice, whose bone marrows have been replaced with bone marrows derived from ROCK1(-/-) mice. Bone marrow-derived ROCK1-deficient macrophages exhibited impaired chemotaxis to monocyte chemotactic protein-1 and showed reduced ability to take up lipids and to develop into foam cells when exposed to modified low-density lipoprotein. These findings indicate that ROCK1 in bone marrow-derived cells is a critical mediator of atherogenesis and suggest that macrophage ROCK1 may be an important therapeutic target for vascular inflammation and atherosclerosis.
| S-EPMC2537434 | biostudies-literature
Project description:CETP activity reduces plasma HDL-cholesterol concentrations, a correlate of an increased risk of atherosclerotic events. However, our recent findings suggest that CETP expression in macrophages promotes an intracellular antioxidant state, reduces free cholesterol accumulation and phagocytosis, and attenuates pro-inflammatory gene expression. To determine whether CETP expression in macrophages affects atherosclerosis development, we transplanted bone marrow from transgenic mice expressing simian CETP or non-expressing littermates into hypercholesterolemic LDL-receptor-deficient mice. The CETP expression did not change the lipid-stained lesion areas but decreased the macrophage content (CD68), neutrophil accumulation (LY6G), and TNF-α aorta content of young male transplanted mice and decreased LY6G, TNF-α, iNOS, and nitrotyrosine (3-NT) in aged female transplanted mice. These findings suggest that CETP expression in bone-marrow-derived cells reduces the inflammatory features of atherosclerosis. These novel mechanistic observations may help to explain the failure of CETP inhibitors in reducing atherosclerotic events in humans.
| S-EPMC10605246 | biostudies-literature
Project description: Not available
| S-EPMC4684322 | biostudies-literature
Project description:Bone marrow transplantation (BMT) involves conditioning regimens which acutely induce side effects, including systemic inflammation, intestinal damage and shifts in the gut microbial composition, some of which may persist chronically. As the gut microbiota affect systemic immune responses, we aimed to investigate whether, post-BMT, the peripheral immune system is modulated as a direct consequence of alterations in the gut microbiota. We show that 24 weeks post-BMT, splenocytes but not peritoneal macrophages display increased cytokine response patterns upon ex-vivo stimulation with various pathogens as compared to untreated controls. The pattern of BMT-induced cytokine responses was transferred to splenocytes, and not to peritoneal macrophages, of healthy controls via co-housing and transferred to germfree mice via transplantation of cecum content. Thus, BMT induces changes in gut microbiota that in their turn increase cytokine responsiveness of splenocytes. Thus, BMT establishes a dominant microbiota that attenuates normalization of the immune-response.
| S-EPMC9046407 | biostudies-literature
Project description:RationaleHyperhomocysteinemia (HHcy) accelerates atherosclerosis and increases inflammatory monocytes (MC) in peripheral tissues. However, its causative role in atherosclerosis is not well established and its effect on vascular inflammation has not been studied. The underlying mechanism is unknown.ObjectiveThis study examined the causative role of HHcy in atherogenesis and its effect on inflammatory MC differentiation.Methods and resultsWe generated a novel HHcy and hyperlipidemia mouse model, in which cystathionine β-synthase (CBS) and low-density lipoprotein receptor (LDLr) genes were deficient (Ldlr(-/-) Cbs(-/+)). Severe HHcy (plasma homocysteine (Hcy)=275 μmol/L) was induced by a high methionine diet containing sufficient basal levels of B vitamins. Plasma Hcy levels were lowered to 46 μmol/L from 244 μmol/L by vitamin supplementation, which elevated plasma folate levels. Bone marrow (BM)-derived cells were traced by the transplantation of BM cells from enhanced green fluorescent protein (EGFP) transgenic mice after sublethal irradiation of the recipient. HHcy accelerated atherosclerosis and promoted Ly6C(high) inflammatory MC differentiation of both BM and tissue origins in the aortas and peripheral tissues. It also elevated plasma levels of TNF-α, IL-6, and MCP-1; increased vessel wall MC accumulation; and increased macrophage maturation. Hcy-lowering therapy reversed HHcy-induced lesion formation, plasma cytokine increase, and blood and vessel inflammatory MC (Ly6C(high+middle)) accumulation. Plasma Hcy levels were positively correlated with plasma levels of proinflammatory cytokines. In primary mouse splenocytes, L-Hcy promoted rIFNγ-induced inflammatory MC differentiation, as well as increased TNF-α, IL-6, and superoxide anion production in inflammatory MC subsets. Antioxidants and folic acid reversed L-Hcy-induced inflammatory MC differentiation and oxidative stress in inflammatory MC subsets.ConclusionsHHcy causes vessel wall inflammatory MC differentiation and macrophage maturation of both BM and tissue origins, leading to atherosclerosis via an oxidative stress-related mechanism.
| S-EPMC3412115 | biostudies-literature
Project description:The central physiological role of the bone marrow renders bone marrow stromal cells (BMSCs) particularly sensitive to aging. With bone aging, BMSCs acquire a differentiation potential bias in favor of adipogenesis over osteogenesis, and the underlying molecular mechanisms remain unclear. Herein, we investigated the factors underlying age-related changes in the bone marrow and their roles in BMSCs' differentiation. Antibody array revealed that CC chemokine ligand 3 (CCL3) accumulation occurred in the serum of naturally aged mice along with bone aging phenotypes, including bone loss, bone marrow adiposity, and imbalanced BMSC differentiation. In vivo Ccl3 deletion could rescue these phenotypes in aged mice. CCL3 improved the adipogenic differentiation potential of BMSCs, with a positive feedback loop between CCL3 and C/EBPα. CCL3 activated C/EBPα expression via STAT3, while C/EBPα activated CCL3 expression through direct promoter binding, facilitated by DNA hypomethylation. Moreover, CCL3 inhibited BMSCs' osteogenic differentiation potential by blocking β-catenin activity mediated by ERK-activated Dickkopf-related protein 1 upregulation. Blocking CCL3 in vivo via neutralizing antibodies ameliorated trabecular bone loss and bone marrow adiposity in aged mice. This study provides insights regarding age-related bone loss and bone marrow adiposity pathogenesis and lays a foundation for the identification of new targets for senile osteoporosis treatment.
| S-EPMC9870077 | biostudies-literature
Project description:PURPOSE: Alternative cell sources have been sought for the treatment of liver diseases, since liver cells are in short supply for cell transplantation. Although bone marrow-derived cells have been investigated as an alternative cell source, few studies have demonstrated long-term disease correction. Here we examined bone marrow stem cell transplantation into the toxic milk (tx) mouse model for Wilson's disease, a mild liver disease characterized by hepatic copper accumulation. The aim of this study was to determine whether bone marrow cells engrafted in the liver could sustain correction of abnormal copper metabolism in the tx mouse. METHODS: Bone marrow cells were isolated from congenic normal mice, transduced to express enhanced green fluorescent protein, sorted for stem cell (Sca-1) and lineage cell (Lin) surface markers, and then transplanted into sub-lethally irradiated normal or tx mice. Analysis for donor cell activity and distribution was undertaken 5 and 9 months post-transplant to allow for sufficient time to repopulate the liver and demonstrate disease correction. RESULTS: Donor bone marrow cells engrafted in both normal and tx mouse liver within 5 months. Significantly reduced liver copper was found in tx mice with donor cell liver engraftment at 5 months post-transplant compared to controls, demonstrating partial correction of abnormal copper metabolism in the short term. However, disease correction was not maintained 9 months post-transplantation. Lin(-)Sca-1(+) cells were more likely to partially correct disease than Lin(+)Sca-1(-) cells in the short term. CONCLUSION: These results demonstrate that bone marrow transplants cannot maintain disease correction in a mouse model of mild hepatic damage, although initial copper metabolism correction was observed.
| S-EPMC2716861 | biostudies-other
Project description:Objective: To explore the role of bone marrow adipocytes (BMAds) in osteoarthritis (OA). Methods: Male and female C57BL/6 mice (n=4/group) underwent meniscectomy (MNX) or SHAM surgery. OA was determined using OARSI score and the number of perilipin+ adipocytes was quantified. Mesenchymal Stromal Cells (MSCs) from MNX and SHAM mice were differentiated into osteoblasts and adipocytes. Human adipocytes and MSCs (n=8) were enzymatically isolated from epiphyseal and metaphyseal marrow, and from subcutaneous adipose tissue (SCAT) of hip OA patients. Human OA MSCs were differentiated into osteoblasts and adipocytes (OA-Diff-hAdipo). Gene expression patterns of epiphyseal and metaphyseal BMAds, SCAT adipocytes and OA-Diff-hAdipo were evaluated by RNAseq (n=4). The effect conditioned media from OA epiphyseal bone (n=5) on the alkaline phosphatase (ALP) activity and mineralization kinetics was assessed in vitro. Results: Increase in BMAd density was positively correlated with cartilage degradation in MNX mice. OA modified the differentiation capacity of MSCs, accelerating adipocyte differentiation and failing to produce osteoblasts in both human and mice. Human epiphyseal, metaphyseal and SCAT adipocytes from the same OA patients each displayed a specific transcriptome, suggesting different functions. Enrichment analysis defined metaphyseal OA-BMAds as cells implicated in hematopoietic stem cell differentiation. On the other hand, epiphyseal OA-BMAds were considered as osteogenic cells showing an up-regulation of genes related to bone mineralization and remodeling. Specifically, OA epiphysis-secreted molecules decreased ALP activity and altered in vitro the mineralization process. Conclusion: All these results support the emergence of BMAds as new cell partners in OA, opening new venues for therapeutic approaches.
2025-03-13 | GSE291355 | GEO
Project description:ObjectivesFoxO proteins are transcription factors involved in varieties of cellular processes, including immune cell homeostasis, cytokine production, anti-oxidative stress, and cell proliferation and differentiation. Although these processes are implicated in the development of atherosclerosis, very little is known about the role of FoxO proteins in the context of atherosclerosis. Our objectives were to determine whether and how inactivation of Foxo4, a member of the FoxO family, in vivo promotes atherosclerosis.Methods and resultsApolipoprotein E-deficient (apoE(-/-)) mice were crossbred with animals lacking Foxo4 (Foxo4(-/-)). After 10 weeks on a high fat diet (HFD), Foxo4(-/-)apoE(-/-) mice showed elevated atherosclerosis and increased amount of macrophages and T cells in the plaque compared to apoE(-/-) mice. Bone marrow transplantations of chimeric C57B/6 mice reconstituted with either wild-type or Foxo4(-/-) bone marrows indicate that Foxo4-deficiency in bone marrow derived cells sufficiently promoted atherosclerosis. Foxo4-null macrophages produced elevated inflammatory cytokine IL-6 and levels of reactive oxygen species (ROS) in response to lipopolysaccharides in vitro. Serum levels of IL-6 were upregulated in HFD-fed Foxo4(-/-)apoE(-/-) mice compared to those of apoE(-/-) mice.ConclusionsFoxO4 inhibits atherosclerosis through bone marrow derived cells, possibly by inhibition of ROS and inflammatory cytokines that promote monocyte recruitment and/or retention.
| S-EPMC3226872 | biostudies-literature