scholarly journals Cellular Mechanisms of Tissue Fibrosis. 1. Common and organ-specific mechanisms associated with tissue fibrosis

2013 ◽  
Vol 304 (3) ◽  
pp. C216-C225 ◽  
Author(s):  
Michael Zeisberg ◽  
Raghu Kalluri
Keyword(s):  
Bone Marrow ◽  
Organ Function ◽  
Cellular Mechanisms ◽  
Tissue Fibrosis ◽  
The Future ◽  
Organ Specific ◽  
Kidney Liver

Fibrosis is a pathological scarring process that leads to destruction of organ architecture and impairment of organ function. Chronic loss of organ function in most organs, including bone marrow, heart, intestine, kidney, liver, lung, and skin, is associated with fibrosis, contributing to an estimated one third of natural deaths worldwide. Effective therapies to prevent or to even reverse existing fibrotic lesions are not yet available in any organ. There is hope that an understanding of common fibrosis pathways will lead to development of antifibrotic therapies that are effective in all of these tissues in the future. Here we review common and organ-specific pathways of tissue fibrosis.

scholarly journals Diastolic dysfunction in a pre-clinical model of diabetes is associated with changes in the cardiac non-myocyte cellular composition

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Charles D. Cohen ◽  
Miles J. De Blasio ◽  
Man K. S. Lee ◽  
Gabriella E. Farrugia ◽  
Darnel Prakoso ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Diastolic Dysfunction ◽  
Systolic Function ◽  
Cardiac Fibroblasts ◽  
Detailed Examination ◽  
Diabetic Mice ◽  
Cellular Mechanisms ◽  
Clinical Model ◽  
Cardiac Ventricles

Abstract Background Diabetes is associated with a significantly elevated risk of cardiovascular disease and its specific pathophysiology remains unclear. Recent studies have changed our understanding of cardiac cellularity, with cellular changes accompanying diabetes yet to be examined in detail. This study aims to characterise the changes in the cardiac cellular landscape in murine diabetes to identify potential cellular protagonists in the diabetic heart. Methods Diabetes was induced in male FVB/N mice by low-dose streptozotocin and a high-fat diet for 26-weeks. Cardiac function was measured by echocardiography at endpoint. Flow cytometry was performed on cardiac ventricles as well as blood, spleen, and bone-marrow at endpoint from non-diabetic and diabetic mice. To validate flow cytometry results, immunofluorescence staining was conducted on left-ventricles of age-matched mice. Results Mice with diabetes exhibited hyperglycaemia and impaired glucose tolerance at endpoint. Echocardiography revealed reduced E:A and e’:a’ ratios in diabetic mice indicating diastolic dysfunction. Systolic function was not different between the experimental groups. Detailed examination of cardiac cellularity found resident mesenchymal cells (RMCs) were elevated as a result of diabetes, due to a marked increase in cardiac fibroblasts, while smooth muscle cells were reduced in proportion. Moreover, we found increased levels of Ly6Chi monocytes in both the heart and in the blood. Consistent with this, the proportion of bone-marrow haematopoietic stem cells were increased in diabetic mice. Conclusions Murine diabetes results in distinct changes in cardiac cellularity. These changes—in particular increased levels of fibroblasts—offer a framework for understanding how cardiac cellularity changes in diabetes. The results also point to new cellular mechanisms in this context, which may further aid in development of pharmacotherapies to allay the progression of cardiomyopathy associated with diabetes.

Analysis of hypoxia-associated dendritic cells in colitic mice and effects of probiotics on IL-10 production in inflammatory dendritic-cells under hypoxia

2019 ◽  
Vol 10 (7) ◽  
pp. 801-810
Author(s):  
T. Ogita ◽  
J. Miyamoto ◽  
Y. Hirabayashi ◽  
M. Rossi ◽  
G. Mazzarella ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Hypoxia Inducible Factor ◽  
Flow Cytometric Analysis ◽  
Bifidobacterium Bifidum ◽  
Sodium Sulphate ◽  
Mesenteric Lymph Nodes ◽  
Cellular Mechanisms ◽  
Hypoxic Conditions ◽  
Anti Inflammatory

The aim of this study was to analyse hypoxia-associated dendritic cells (DCs) in colitic mice and the effects of probiotics on interleukin (IL)-10 production in inflammatory DCs under hypoxic conditions. Extensive hypoxia was observed in the colonic mucosa of dextran sodium sulphate-induced colitic mice. Flow cytometric analysis demonstrated that hypoxia-inducible factor-1α+ DCs in colonic lamina propria (CLP) lymphocytes and mesenteric lymph nodes (MLN) were more abundant in colitic mice than those in controls. Among three subsets of DCs, i.e. plasmacytoid DCs, conventional DCs (cDCs), and monocyte-derived DCs (mDCs), cDCs and mDCs were more abundant in CLP of colitic mice. Bone marrow-derived Flt-3L-induced DCs (Flt-DCs) but not bone marrow-derived GM-CSF-induced DCs (GM-DCs), incubated with 1% O2 exhibited an inflammatory phenotype, with higher CD86, IL-6, and tumour necrosis factor-α expression, and lower IL-10 levels than those in Flt-DCs incubated with 21% O2. The hypoxia-induced decrease in IL-10 expression in Flt-DCs was restored by Bifidobacterium bifidum JCM 1255T promoted IL-10 expression through the p38 pathway under normoxic conditions. The anti-inflammatory effects of B. bifidum JCM 1255T in Flt-DCs were mediated through different cellular mechanisms under hypoxic and normoxic conditions. B. bifidum JCM 1255T could be used therapeutically for its anti-inflammatory effects.

scholarly journals Atlas of Age- and Tissue-specific DNA Methylation during Early Development of Barley (Hordeum vulgare)

2018 ◽  
Author(s):  
Moumouni Konate ◽  
Michael J. Wilkinson ◽  
Banjamin Mayne ◽  
Eileen Scott ◽  
Bettina Berger ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Hordeum Vulgare ◽  
Organ Function ◽  
Tissue Specific ◽  
Organ Differentiation ◽  
Differentiated Cells ◽  
Differentially Methylated Genes ◽  
Organ Specific ◽  
Development And Differentiation ◽  
Methylation Patterns

The barley (Hordeum vulgare) genome comprises over 32,000 genes, with differentiated cells expressing only a subset of genes; the remainder being silent. Mechanisms by which tissue-specific genes are regulated are not entirely understood, although DNA methylation is likely to be involved. DNA methylation patterns are not static during plant development, but it is still unclear whether different organs possess distinct methylation profiles. Methylation-sensitive GBS was used to generate DNA methylation profiles for roots, leaf-blades and leaf-sheaths from five barley varieties, using seedlings at the three-leaf stage. Differentially Methylated Markers (DMMs) were characterised by pairwise comparisons of roots, leaf-blades and leaf-sheaths of three different ages. While very many DMMs were found between roots and leaf parts, only a few existed between leaf-blades and leaf-sheaths, with differences decreasing with leaf rank. Organ-specific DMMs appeared to target mainly repeat regions, implying that organ differentiation partially relies on the spreading of DNA methylation from repeats to promoters of adjacent genes. Furthermore, the biological functions of differentially methylated genes in the different organs correlated with functional specialisation. Our results indicate that different organs do possess diagnostic methylation profiles and suggest that DNA methylation is important for both tissue development and differentiation and organ function.

scholarly journals Legionella pneumophila Evades Gamma Interferon-Mediated Growth Suppression through Interleukin-10 Induction in Bone Marrow-Derived Macrophages

2005 ◽  
Vol 73 (5) ◽  
pp. 2709-2717 ◽  
Author(s):  
Sadako Yoshizawa ◽  
Kazuhiro Tateda ◽  
Tetsuya Matsumoto ◽  
Fumio Gondaira ◽  
Shuichi Miyazaki ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cross Talk ◽  
Legionella Pneumophila ◽  
Interleukin 10 ◽  
Gamma Interferon ◽  
Protein Component ◽  
Interleukin 12 ◽  
Cellular Mechanisms ◽  
Ifn Γ ◽  
Culture Supernatants

ABSTRACT We examined the roles of Th1-Th2 cytokine cross talk in Legionella pneumophila-infected bone marrow-derived (BM) macrophages in the presence of costimulation with interleukin-12 (IL-12) and IL-18. Treatment with gamma interferon (IFN-γ) alone or treatment with IL-12 in combination with IL-18 resulted in a 3- or 2-log reduction in bacterial numbers, respectively, in BM macrophages, whereas treatment with IL-12 or IL-18 alone had no effect. Significant amounts of IFN-γ were detected in the culture supernatants of infected macrophages stimulated with IL-12 and IL-18 in combination but not independently. Neutralization of IFN-γ by antibody completely abolished the growth inhibitory effects of IL-12 and IL-18. Interestingly, higher infectivity ratios of L. pneumophila or the addition of increasing concentrations of heat-killed bacteria (HKB) suppressed the production of IFN-γ, which resulted in the increased intracellular growth of bacteria. Significant amounts of IL-10 were detected in culture supernatants when Legionella-infected macrophages were cocultured with HKB. Furthermore, neutralization of IL-10 by antibody resulted in an increase in IFN-γ production by infected BM macrophages when cocultured with HKB. Treatment of HKB with trypsin but not polymyxin B attenuated the growth-promoting effects of HKB, suggesting the involvement of a protein component(s) in regulation of the growth of L. pneumophila. These findings demonstrate a crucial role of Th1-Th2 cross talk in L. pneumophila-infected BM macrophages. Our results also suggest that L. pneumophila modulates the cytokine balance from IFN-γ-driven Th1 to more Th2 responses, likely through the induction of IL-10 by a bacterial protein component(s). These data provide new insights not only into the cellular mechanisms of Th1-Th2 cross talk in Legionella-infected macrophages but also into the pathogenesis of L. pneumophila pneumonia in humans.

scholarly journals Thymus and autoimmunity: capacity of the normal thymus to produce pathogenic self-reactive T cells and conditions required for their induction of autoimmune disease.

1990 ◽  
Vol 172 (2) ◽  
pp. 537-545 ◽  
Author(s):  
S Sakaguchi ◽  
N Sakaguchi
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Autoimmune Disease ◽  
Autoimmune Diseases ◽  
Rheumatoid Factors ◽  
Systemic Autoimmune Diseases ◽  
Organ Specific ◽  
Gastric Parietal Cells

BALB/c athymic nu/nu mice spontaneously developed organ-specific (gastritis, thyroiditis, oophoritis, or orchitis) and systemic (arteritis, glomerulonephritis, and polyarthritis) autoimmune diseases when transplanted with neonatal BALB/c thymuses. Transplantation of thymuses from adult BALB/c mice was far less effective in inducing histologically evident organ-specific autoimmune disease in nu/nu mice. Autoimmune disease developed, however, when adult thymuses were irradiated at a T cell-depleting dose before transplantation. Engrafting newborn thymuses into BALB/c mice T cell depleted by thymectomy, irradiation, and bone marrow transplantation produced similar organ-specific autoimmune disease as well, but thymus engrafting into T cell-nondepleted BALB/c mice (i.e., mice thymectomized as adults, but not irradiated) did not, despite the fact that transplanted thymuses grew well in both groups of mice. The mice with organ-specific autoimmune disease produced autoantibodies specific for the respective organ components, such as gastric parietal cells, thyroglobulins, oocytes, or sperm. The thymus-transplanted nu/nu mice also had hypergammaglobulinemia and developed anti-DNA autoantibodies, rheumatoid factors, and immune complexes in the circulation. These results indicate that: (a) the thymus of a murine strain that does not develop spontaneous autoimmune disease can produce pathogenic self-reactive T cells that mediate organ-specific and/or systemic autoimmune diseases; and (b) such self-reactive T cells, especially those mediating organ-specific autoimmune disease, spontaneously expand and cause autoimmune disease when released to the T cell-deficient or -eliminated periphery.

scholarly journals Maintenance of hemopoietic stem cells and production of differentiated progeny in allogeneic and semiallogeneic bone marrow chimeras in vitro.

1977 ◽  
Vol 145 (6) ◽  
pp. 1612-1616 ◽  
Author(s):  
T M Dexter ◽  
M A Moore ◽  
A P Sheridan
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Culture System ◽  
Adherent Cells ◽  
Cellular Mechanisms ◽  
Graft Versus Host ◽  
Proliferation And Differentiation ◽  
Bone Marrow Chimeras

A culture system is described in which bone marrow-derived adherent cells can support prolonged proliferation and differentiation of genetically incompatible stem cells and precursor cells. The results suggest that the reactive cells responsible in vivo for host transplantation resistance and for graft-versus-host disease are selectively lost or inhibited in such cultures, which may provide a vehicle for studying some of the cellular mechanisms involved in transplantation resistance.

scholarly journals Cellular Mechanisms of Tissue Fibrosis. 8. Current and future drug targets in fibrosis: focus on Rho GTPase-regulated gene transcription

2014 ◽  
Vol 307 (1) ◽  
pp. C2-C13 ◽  
Author(s):  
Pei-Suen Tsou ◽  
Andrew J. Haak ◽  
Dinesh Khanna ◽  
Richard R. Neubig
Keyword(s):  
Growth Factor ◽  
Gene Transcription ◽  
Drug Targets ◽  
Transforming Growth Factor ◽  
Serum Response Factor ◽  
Rho Gtpase ◽  
Tissue Growth ◽  
Cellular Mechanisms ◽  
Tissue Fibrosis ◽  
Matrix Deposition

Tissue fibrosis occurs with excessive extracellular matrix deposition from myofibroblasts, resulting in tissue scarring and inflammation. It is driven by multiple mediators, such as the G protein-coupled receptor ligands lysophosphatidic acid and endothelin, as well as signaling by transforming growth factor-β, connective tissue growth factor, and integrins. Fibrosis contributes to 45% of deaths in the developed world. As current therapeutic options for tissue fibrosis are limited and organ transplantation is the only effective treatment for end-stage disease, there is an imminent need for efficacious antifibrotic therapies. This review discusses the various molecular pathways involved in fibrosis. It highlights the Rho GTPase signaling pathway and its downstream gene transcription output through myocardin-related transcription factor and serum response factor as a convergence point for targeting this complex set of diseases.

scholarly journals Interorgan Coordination of the Murine Adaptive Response to Fasting

2011 ◽  
Vol 286 (18) ◽  
pp. 16332-16343 ◽  
Author(s):  
Theodorus B. M. Hakvoort ◽  
Perry D. Moerland ◽  
Raoul Frijters ◽  
Aleksandar Sokolović ◽  
Wilhelmina T. Labruyère ◽  
...  
Keyword(s):  
Small Intestine ◽  
Transcription Factors ◽  
Adaptive Response ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Network Analyses ◽  
Complex Adaptive ◽  
Organ Specific ◽  
Liver And Kidney ◽  
Kidney Liver

Starvation elicits a complex adaptive response in an organism. No information on transcriptional regulation of metabolic adaptations is available. We, therefore, studied the gene expression profiles of brain, small intestine, kidney, liver, and skeletal muscle in mice that were subjected to 0–72 h of fasting. Functional-category enrichment, text mining, and network analyses were employed to scrutinize the overall adaptation, aiming to identify responsive pathways, processes, and networks, and their regulation. The observed transcriptomics response did not follow the accepted “carbohydrate-lipid-protein” succession of expenditure of energy substrates. Instead, these processes were activated simultaneously in different organs during the entire period. The most prominent changes occurred in lipid and steroid metabolism, especially in the liver and kidney. They were accompanied by suppression of the immune response and cell turnover, particularly in the small intestine, and by increased proteolysis in the muscle. The brain was extremely well protected from the sequels of starvation. 60% of the identified overconnected transcription factors were organ-specific, 6% were common for 4 organs, with nuclear receptors as protagonists, accounting for almost 40% of all transcriptional regulators during fasting. The common transcription factors were PPARα, HNF4α, GCRα, AR (androgen receptor), SREBP1 and -2, FOXOs, EGR1, c-JUN, c-MYC, SP1, YY1, and ETS1. Our data strongly suggest that the control of metabolism in four metabolically active organs is exerted by transcription factors that are activated by nutrient signals and serves, at least partly, to prevent irreversible brain damage.

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