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Osteopontin and iCD8α Cells Promote Intestinal Intraepithelial Lymphocyte Homeostasis.
Nazmi A, Greer MJ, Hoek KL, Piazuelo MB, Weitkamp JH, Olivares-Villagómez D
(2020) J Immunol 204: 1968-1981
MeSH Terms: Animals, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Epithelium, Female, Homeostasis, Humans, Hyaluronan Receptors, Intestines, Intraepithelial Lymphocytes, Killer Cells, Natural, Male, Mice, Mice, Inbred C57BL, Osteopontin, Receptors, Antigen, T-Cell, gamma-delta, Th17 Cells
Show Abstract · Added February 28, 2020
Intestinal intraepithelial lymphocytes (IEL) comprise a diverse population of cells residing in the epithelium at the interface between the intestinal lumen and the sterile environment of the lamina propria. Because of this anatomical location, IEL are considered critical components of intestinal immune responses. Indeed, IEL are involved in many different immunological processes, ranging from pathogen control to tissue stability. However, despite their critical importance in mucosal immune responses, very little is known about the homeostasis of different IEL subpopulations. The phosphoprotein osteopontin is important for critical physiological processes, including cellular immune responses, such as survival of Th17 cells and homeostasis of NK cells among others. Because of its impact in the immune system, we investigated the role of osteopontin in the homeostasis of IEL. In this study, we report that mice deficient in the expression of osteopontin exhibit reduced numbers of the IEL subpopulations TCRγδ, TCRβCD4, TCRβCD4CD8α, and TCRβCD8αα cells in comparison with wild-type mice. For some IEL subpopulations, the decrease in cell numbers could be attributed to apoptosis and reduced cell division. Moreover, we show in vitro that exogenous osteopontin stimulates the survival of murine IEL subpopulations and unfractionated IEL derived from human intestines, an effect mediated by CD44, a known osteopontin receptor. We also show that iCD8α IEL but not TCRγδ IEL, TCRβ IEL, or intestinal epithelial cells, can promote survival of different IEL populations via osteopontin, indicating an important role for iCD8α cells in the homeostasis of IEL.
Copyright © 2020 by The American Association of Immunologists, Inc.
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17 MeSH Terms
Inactivation of mTORC2 in macrophages is a signature of colorectal cancer that promotes tumorigenesis.
Katholnig K, Schütz B, Fritsch SD, Schörghofer D, Linke M, Sukhbaatar N, Matschinger JM, Unterleuthner D, Hirtl M, Lang M, Herac M, Spittler A, Bergthaler A, Schabbauer G, Bergmann M, Dolznig H, Hengstschläger M, Magnuson MA, Mikula M, Weichhart T
(2019) JCI Insight 4:
MeSH Terms: Animals, Carcinogenesis, Cell Line, Tumor, Cell Proliferation, Cells, Cultured, Colitis, Ulcerative, Colon, Colorectal Neoplasms, Dextran Sulfate, Disease Models, Animal, Female, Humans, Intestinal Mucosa, Kaplan-Meier Estimate, Macrophages, Male, Mechanistic Target of Rapamycin Complex 2, Mice, Mice, Transgenic, Morpholines, Osteopontin, Primary Cell Culture, Prognosis, Survival Rate
Show Abstract · Added November 6, 2019
The mechanistic target of rapamycin complex 2 (mTORC2) is a potentially novel and promising anticancer target due to its critical roles in proliferation, apoptosis, and metabolic reprogramming of cancer cells. However, the activity and function of mTORC2 in distinct cells within malignant tissue in vivo is insufficiently explored. Surprisingly, in primary human and mouse colorectal cancer (CRC) samples, mTORC2 signaling could not be detected in tumor cells. In contrast, only macrophages in tumor-adjacent areas showed mTORC2 activity, which was downregulated in stromal macrophages residing within human and mouse tumor tissues. Functionally, inhibition of mTORC2 by specific deletion of Rictor in macrophages stimulated tumorigenesis in a colitis-associated CRC mouse model. This phenotype was driven by a proinflammatory reprogramming of mTORC2-deficient macrophages that promoted colitis via the cytokine SPP1/osteopontin to stimulate tumor growth. In human CRC patients, high SPP1 levels and low mTORC2 activity in tumor-associated macrophages correlated with a worsened clinical prognosis. Treatment of mice with a second-generation mTOR inhibitor that inhibits mTORC2 and mTORC1 exacerbated experimental colorectal tumorigenesis in vivo. In conclusion, mTORC2 activity is confined to macrophages in CRC and limits tumorigenesis. These results suggest activation but not inhibition of mTORC2 as a therapeutic strategy for colitis-associated CRC.
1 Communities
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24 MeSH Terms
Osteopontin activates the diabetes-associated potassium channel TALK-1 in pancreatic β-cells.
Dickerson MT, Vierra NC, Milian SC, Dadi PK, Jacobson DA
(2017) PLoS One 12: e0175069
MeSH Terms: Aged, Animals, Calcium Signaling, Diabetes Mellitus, Type 2, Female, Glucose, HEK293 Cells, Humans, Insulin, Insulin Secretion, Insulin-Secreting Cells, Membrane Potentials, Mice, Knockout, Osteopontin, Potassium, Potassium Channels, Tandem Pore Domain
Show Abstract · Added November 13, 2017
Glucose-stimulated insulin secretion (GSIS) relies on β-cell Ca2+ influx, which is modulated by the two-pore-domain K+ (K2P) channel, TALK-1. A gain-of-function polymorphism in KCNK16, the gene encoding TALK-1, increases risk for developing type-2 diabetes. While TALK-1 serves an important role in modulating GSIS, the regulatory mechanism(s) that control β-cell TALK-1 channels are unknown. Therefore, we employed a membrane-specific yeast two-hybrid (MYTH) assay to identify TALK-1-interacting proteins in human islets, which will assist in determining signaling modalities that modulate TALK-1 function. Twenty-one proteins from a human islet cDNA library interacted with TALK-1. Some of these interactions increased TALK-1 activity, including intracellular osteopontin (iOPN). Intracellular OPN is highly expressed in β-cells and is upregulated under pre-diabetic conditions to help maintain normal β-cell function; however, the functional role of iOPN in β-cells is poorly understood. We found that iOPN colocalized with TALK-1 in pancreatic sections and coimmunoprecipitated with human islet TALK-1 channels. As human β-cells express two K+ channel-forming variants of TALK-1, regulation of these TALK-1 variants by iOPN was assessed. At physiological voltages iOPN activated TALK-1 transcript variant 3 channels but not TALK-1 transcript variant 2 channels. Activation of TALK-1 channels by iOPN also hyperpolarized resting membrane potential (Vm) in HEK293 cells and in primary mouse β-cells. Intracellular OPN was also knocked down in β-cells to test its effect on β-cell TALK-1 channel activity. Reducing β-cell iOPN significantly decreased TALK-1 K+ currents and increased glucose-stimulated Ca2+ influx. Importantly, iOPN did not affect the function of other K2P channels or alter Ca2+ influx into TALK-1 deficient β-cells. These results reveal the first protein interactions with the TALK-1 channel and found that an interaction with iOPN increased β-cell TALK-1 K+ currents. The TALK-1/iOPN complex caused Vm hyperpolarization and reduced β-cell glucose-stimulated Ca2+ influx, which is predicted to inhibit GSIS.
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16 MeSH Terms
Differential stem- and progenitor-cell trafficking by prostaglandin E2.
Hoggatt J, Mohammad KS, Singh P, Hoggatt AF, Chitteti BR, Speth JM, Hu P, Poteat BA, Stilger KN, Ferraro F, Silberstein L, Wong FK, Farag SS, Czader M, Milne GL, Breyer RM, Serezani CH, Scadden DT, Guise TA, Srour EF, Pelus LM
(2013) Nature 495: 365-9
MeSH Terms: Animals, Anti-Inflammatory Agents, Non-Steroidal, Cell Count, Cell Movement, Cells, Cultured, Dinoprostone, Hematopoietic Stem Cell Mobilization, Hematopoietic Stem Cells, Heterocyclic Compounds, Humans, Meloxicam, Mice, Mice, Inbred C57BL, Mice, Knockout, Osteopontin, Papio, Receptors, Prostaglandin E, EP4 Subtype, Stem Cells, Thiazines, Thiazoles
Show Abstract · Added December 21, 2013
To maintain lifelong production of blood cells, haematopoietic stem cells (HSCs) are tightly regulated by inherent programs and extrinsic regulatory signals received from their microenvironmental niche. Long-term repopulating HSCs reside in several, perhaps overlapping, niches that produce regulatory molecules and signals necessary for homeostasis and for increased output after stress or injury. Despite considerable advances in the specific cellular or molecular mechanisms governing HSC-niche interactions, little is known about the regulatory function in the intact mammalian haematopoietic niche. Recently, we and others described a positive regulatory role for prostaglandin E2 (PGE2) on HSC function ex vivo. Here we show that inhibition of endogenous PGE2 by non-steroidal anti-inflammatory drug (NSAID) treatment in mice results in modest HSC egress from the bone marrow. Surprisingly, this was independent of the SDF-1-CXCR4 axis implicated in stem-cell migration. Stem and progenitor cells were found to have differing mechanisms of egress, with HSC transit to the periphery dependent on niche attenuation and reduction in the retentive molecule osteopontin. Haematopoietic grafts mobilized with NSAIDs had superior repopulating ability and long-term engraftment. Treatment of non-human primates and healthy human volunteers confirmed NSAID-mediated egress in other species. PGE2 receptor knockout mice demonstrated that progenitor expansion and stem/progenitor egress resulted from reduced E-prostanoid 4 (EP4) receptor signalling. These results not only uncover unique regulatory roles for EP4 signalling in HSC retention in the niche, but also define a rapidly translatable strategy to enhance transplantation therapeutically.
2 Communities
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20 MeSH Terms
New serum markers of hepatocellular carcinoma.
Masuzaki R, Karp SJ, Omata M
(2012) Semin Oncol 39: 434-9
MeSH Terms: Biomarkers, Biomarkers, Tumor, Carcinoma, Hepatocellular, Glypicans, Hepatocyte Growth Factor, Humans, Insulin-Like Growth Factor I, Liver Neoplasms, Osteopontin, Protein Precursors, Prothrombin, Vascular Endothelial Growth Factor A, alpha-Fetoproteins
Show Abstract · Added May 2, 2014
Hepatocellular carcinoma (HCC), one of the most common cancers worldwide, usually develops in a liver already suffering from chronic damages, often cirrhosis. There has been marked progress in the treatment of HCC. However, effective treatments are limited to patients with less advanced HCC. The detection of HCC at an early stage is still a prerequisite for improved prognosis. To address this problem, a variety of screening modalities are used, including measurement of alpha-fetoprotein (AFP) and ultrasonography (US) at regular intervals in high-risk populations. Unfortunately, poor sensitivity and specificity of AFP and the operator-dependency of US limit the value of either test to diagnose early-stage lesions. Other tests, including Lens culinaris agglutinin-reactive AFP and des-gamma carboxyprothrombin (DCP), are currently being evaluated and may be superior to current tests. Recent developments in gene-expressing microarrays and proteomics promise even more potential diagnostic options. The strict application of the Early Detection Research Network methodology will aid in the assessment of their diagnostic utility, and provide an objective basis for the assessment of their clinical utility.
Copyright © 2012 Elsevier Inc. All rights reserved.
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13 MeSH Terms
Osteopontin regulates development and function of invariant natural killer T cells.
Diao H, Iwabuchi K, Li L, Onoe K, Van Kaer L, Kon S, Saito Y, Morimoto J, Denhardt DT, Rittling S, Uede T
(2008) Proc Natl Acad Sci U S A 105: 15884-9
MeSH Terms: Animals, Down-Regulation, Fas Ligand Protein, Interleukin-4, Killer Cells, Natural, Lymphocyte Activation, Mice, Mice, Knockout, Osteopontin, Receptors, KIR, Thymus Gland, Transcription Factors
Show Abstract · Added December 10, 2013
Invariant natural killer T (iNKT) cells belong to a subset of lymphocytes bridging innate and acquired immunity. We demonstrated that osteopontin (OPN) is involved in the activation of iNKT cells. In the present work, we examined whether OPN affects development and function of iNKT cells. We found that the number of peripheral iNKT cells was significantly reduced in OPN-deficient mice compared with wild-type mice. Although the number of thymic iNKT cells was not different between WT and OPN-deficient mice, intrathymic iNKT cell maturation was impaired in OPN-deficient mice. iNKT cell function was also significantly altered in OPN-deficient mice, as evidenced by (i) deficient down-regulation of iNKT cell receptor, (ii) reduction of IL-4 production while preserving production of IFN-gamma, and (iii) reduction of Fas ligand (FasL) expression, leading to reduced Fas/FasL-dependent cytotoxicity against hepatocytes. Importantly, activation of the transcription factors NFAT2 (nuclear factor of activated T cells 2) and GATA-3 was impaired, whereas activation of T-bet was preserved in iNKT cells of OPN-deficient mice. These data collectively indicate that OPN plays a pivotal role not only in the development, but also in the function of iNKT cells.
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12 MeSH Terms
The role of osteopontin in recovery from hind limb ischemia.
Duvall CL, Weiss D, Robinson ST, Alameddine FM, Guldberg RE, Taylor WR
(2008) Arterioscler Thromb Vasc Biol 28: 290-5
MeSH Terms: Animals, Endothelial Cells, Hindlimb, Ischemia, Lower Extremity, Macrophages, Male, Mice, Neovascularization, Physiologic, Osteopontin, Recovery of Function
Show Abstract · Added March 14, 2018
OBJECTIVE - Osteopontin (OPN) is a highly phosphorylated extracellular matrix glycoprotein that is involved in a diversity of biological processes. In the vascular wall, OPN is produced by monocytes/macrophages, endothelial cells, and smooth muscle cells, and it is thought to mediate adhesion, migration, and survival of these cell types. In this study, we hypothesized that OPN plays a critical role in recovery from limb ischemia.
METHODS AND RESULTS - We induced hind limb ischemia in wild-type and OPN-/- mice. OPN-/- mice exhibited significantly delayed recovery of ischemic foot perfusion as determined by LDPI, impaired collateral vessel formation as measured using micro-CT, and diminished functional capacity of the ischemic limb. In the aortic ring assay, normal endothelial cell sprouting was found in OPN-/- mice. However, OPN-/- peritoneal monocytes/macrophages were found to possess significantly reduced migration in response to chemoattraction.
CONCLUSIONS - This study provides evidence that a definitive biological role exists for OPN during ischemic limb revascularization, and we have suggested that this may be driven by impaired monocyte/macrophage migration in OPN-/- mice. These findings provide the first in vivo evidence that OPN may be a key regulator in postnatal vascular growth.
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11 MeSH Terms
Heterozygous disruption of the PTEN promotes intestinal neoplasia in APCmin/+ mouse: roles of osteopontin.
Shao J, Washington MK, Saxena R, Sheng H
(2007) Carcinogenesis 28: 2476-83
MeSH Terms: Adenocarcinoma, Adenoma, Adenomatous Polyposis Coli, Animals, Apoptosis, Cell Line, Transformed, Cell Survival, Colonic Neoplasms, Crosses, Genetic, Genes, ras, Heterozygote, Intestinal Mucosa, Mice, Mice, Transgenic, Mutation, Neoplasm Invasiveness, Osteopontin, PTEN Phosphohydrolase, Phosphatidylinositol 3-Kinases, Signal Transduction
Show Abstract · Added March 5, 2014
The persistent activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is oncogenic and involved in colorectal neoplasia. Mutations of both regulatory subunit and catalytic subunit of PI3K have been demonstrated in colon cancers. In the present study, we show that heterozygous disruption of the phosphatase and tensin homolog (PTEN) tumor suppressor gene promoted tumor progression in APC(min/+) mice. Number and size of intestinal tumors were significantly increased in mice bearing both adenomatous polyposis coli (APC) and PTEN mutations. While APC(min/+)PTEN(+/+) mice developed adenomas, invasive carcinomas developed in APC(min/+)PTEN(+/-) mice. Large tumors often resulted in intestinal intussusception and early death of APC(min/+)PTEN(+/-) mice. Targeted array revealed that osteopontin (OPN) was the leading gene whose expression was strongly induced by deficiency of PTEN. In colon cancer cells, gain-of-function mutation of PI3K robustly increased levels of OPN and treatment with OPN reduced growth factor deprivation-induced programmed cell death. Moreover, OPN expression was strongly increased in Ras-induced transformation of intestinal epithelial cells in a PI3K-dependent manner. Inhibition of OPN expression by specific small interfering RNA reduced uncontrolled growth and invasiveness of Ras-transformed intestinal epithelial cells. Thus, our results suggest that the PI3K pathway promotes the transformation of intestinal adenoma to adenocarcinoma. OPN, a downstream effector of PI3K, protects transformed intestinal epithelial cells from programmed cell death and stimulates their anchorage-independent growth.
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20 MeSH Terms
The conceptus increases secreted phosphoprotein 1 gene expression in the mouse uterus during the progression of decidualization mainly due to its effects on uterine natural killer cells.
Herington JL, Bany BM
(2007) Reproduction 133: 1213-21
MeSH Terms: Animals, Decidua, Deciduoma, Female, Gene Expression, Gene Expression Regulation, Developmental, Interleukin-15, Killer Cells, Natural, Mice, Mice, Inbred Strains, Mice, Knockout, Osteopontin, RNA, Messenger, Uterus
Show Abstract · Added April 10, 2018
Within the mouse endometrium, secreted phosphoprotein 1 (SPP1) gene expression is mainly expressed in the luminal epithelium and some macrophages around the onset of implantation. However, during the progression of decidualization, it is expressed mainly in the mesometrial decidua. To date, the precise cell types responsible for the expression in the mesometrial decidua has not been absolutely identified. The goal of the present study was to assess the expression of SPP1 in uteri of pregnant mice (decidua) during the progression of decidualization and compared it with those undergoing artificially induced decidualization (deciduoma). Significantly (P<0.05) greater steady-state levels of SPP1 mRNA were seen in the decidua when compared with deciduoma. Further, in the decidua, the majority of the SPP1 protein was localized within a subpopulation of granulated uterine natural killer (uNK) cells but not co-localized to their granules. However, in addition to being localized to uNK cells, SPP1 protein was also detected in another cell type(s) that were not epidermal growth factor-like containing mucin-like hormone receptor-like sequence 1 protein-positive immune cells that are known to be present in the uterus at this time. Finally, decidual SPP1 expression dramatically decreased in uteri of interleukin-15-deficient mice that lack uNK cells. In conclusion, SPP1 expression is greater in the mouse decidua when compared with the deciduoma after the onset of implantation during the progression of decidualization. Finally, uNK cells were found to be the major source of SPP1 in the pregnant uterus during decidualization. SPP1 might play a key role in uNK killer cell functions in the uterus during decidualization.
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MeSH Terms
Synthesis and characterization of segmented poly(esterurethane urea) elastomers for bone tissue engineering.
Kavlock KD, Pechar TW, Hollinger JO, Guelcher SA, Goldstein AS
(2007) Acta Biomater 3: 475-84
MeSH Terms: Alkaline Phosphatase, Animals, Biocompatible Materials, Bone and Bones, Cell Count, Cell Culture Techniques, Cells, Cultured, Elastomers, Male, Molecular Structure, Osteocalcin, Osteopontin, Polyurethanes, RNA, Messenger, Rats, Rats, Sprague-Dawley, Stromal Cells, Temperature, Tissue Engineering, Urea
Show Abstract · Added February 23, 2016
Segmented polyurethanes have been used extensively in implantable medical devices, but their tunable mechanical properties make them attractive for examining the effect of biomaterial modulus on engineered musculoskeletal tissue development. In this study, a family of segmented degradable poly(esterurethane urea)s (PEUURs) were synthesized from 1,4-diisocyanatobutane, a poly(epsilon-caprolactone) (PCL) macrodiol soft segment and a tyramine-1,4-diisocyanatobutane-tyramine chain extender. By systematically increasing the PCL macrodiol molecular weight from 1100 to 2700Da, the storage modulus, crystallinity and melting point of the PCL segment were systematically varied. In particular, the melting temperature, T(m), increased from 21 to 61 degrees C and the storage modulus at 37 degrees C increased from 52 to 278MPa with increasing PCL macrodiol molecular weight, suggesting that the crystallinity of the PCL macrodiol contributed significantly to the mechanical properties of the polymers. Bone marrow stromal cells were cultured on rigid polymer films under osteogenic conditions for up to 21 days. Cell density, alkaline phosphatase activity, and osteopontin and osteocalcin expression were similar among PEUURs and comparable to poly(d,l-lactic-coglycolic acid). This study demonstrates the suitability of this family of PEUURs for tissue engineering applications, and establishes a foundation for determining the effect of biomaterial modulus on bone tissue development.
1 Communities
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20 MeSH Terms