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Results for “Cellular Microenvironment”

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PubMed1997

Characterization of the human thymic microenvironment: lymphoepithelial interaction in normal thymus and thymoma.

Recent advances in tissue culture technology and molecular biology have extended our understanding of the functional morphology of the thymus. The importance of a crosstalk between lymphoid cells and stroma has been appreciated as a prerequisite for the normal development of both. The network of direct cellular interactions and soluble factors comprising part of the microenvironment is far from being elucidated but the highly ordered thymic architecture clearly plays a pivotal role in normal thymic function. Insight into the genetic control of stroma development is only emerging while knowledge on the genetic control of the various steps in T cell development is already advanced and rapidly expanding. The present paper gives an overview on the cellular components and matrix molecules of the human thymic microenvironment and their development during ontogeny. The intrathymic cytokine network is shortly reviewed. Special emphasis is put on molecules mediating lymphoepithelial interactions that are necessary for the expansion and early selection of immature thymocytes from precursor cells and for the generation of an MHC restricted and self tolerant T cell repertoire by positive and negative selection. Considering these physiological mechanisms we summarize the molecular pathology of the microenvironment and lymphocyte/stroma interactions in thymic epithelial tumors (thymomas). Finally, a pathogenetic model for paraneoplastic myasthenia gravis is given. We suggest abnormal auto-antigen-specific positive selection of naive T cells as the essential molecular mechanism by which thymomas contribute to the autoimmunization against the acetylcholine receptor and other muscle proteins.

Apoptosis↗

PubMed1986

Characterization of the in vitro stromal microenvironment of human bone marrow.

Utilizing long-term in vitro culture techniques, we characterized the cellular composition and functional attributes of the human in vitro bone marrow stromal microenvironment. Morphologic, specific cytochemical and immunologic methods demonstrated that the marrow stromal adherent layer (AL) reached confluency at two to three weeks, and was comprised of 60%-70% fibroblastic cells, 10%-20% endothelial cells, 10%-20% monocyte/macrophages and 5%-10% fat-laden adherent cells. These proportions of cell types persisted for at least three months concomitant with proliferation of CFU-gm and BFU-e. In contrast, umbilical cord blood cells did not form a stromal AL despite persistence of hemopoietic progenitor cell proliferation. These findings provide a basis for improved understanding of cellular interactions regulating hemopoiesis.

Bone Marrow Cells↗

PubMed2001

Abnormal bone marrow stroma in mice deficient for nemo-like kinase, Nlk.

The stromal compartment of the bone marrow is composed of various cell types that provide trophic and instructive signals for hematopoiesis. The mesenchymal stem cell is believed to give rise to all major cellular components of the bone marrow microenvironment. Nemo-like kinase, Nlk, is a serine-threonine kinase that connects MAP kinase and Wnt signaling pathways; its in vivo function in mouse is unknown. We have generated mice with a targeted disruption of Nlk and find that the complex phenotype significantly varies with the genetic background. Whereas C57BL/6 mice lacking Nlk die during the third trimester of pregnancy, the 129/Sv background supports survival into adolescence; such mice are growth retarded and suffer from various neurological abnormalities. We show here that the Nlk deficiency syndrome includes aberrant differentiation of bone marrow stromal cells. Varying degrees of morphological abnormality, such as increased numbers of adipocytes, large blood sinuses and absence of bone-lining cells are observed in the bone marrow of mutant mice. Nlk deficient mice thus provide a novel model to study the genetic requirements for bone marrow stromal differentiation.

Animals↗

PubMed2006

Intracellular water homeostasis and the mammalian cellular osmotic stress response.

The cellular response to osmotic stress ensures that the concentration of water inside the cell is maintained within a range that is compatible with biologic function. Single cell organisms are particularly dependent on mechanisms that permit adaptation to osmotic stress because each individual cell is directly exposed to the external environment. Mammals, however, limit osmotic stress by establishing an internal aqueous environment in which intravascular water and electrolytes are subject to sensitive and dynamic, organism-based homeostatic regulation. Recent studies of NFAT5/TonEBP, an essential mammalian osmoregulatory transcription factor, demonstrate the unexpected yet critical significance of cell-based osmotic regulation in vivo. These results highlight the fundamental importance of maintaining intracellular water homeostasis in the face of varying cellular metabolic activity and distinct tissue microenvironments.

Animals↗

PubMed1993

From HIV infection to AIDS: are the manifestations of effective immune resistance misinterpreted?

Viewing the immune system as part of an adaptive communication network, rather than merely a coalition of effectors, we argue that the alterations in the immune system that occur in HIV-infected patients, generally considered to be "abnormalities," cannot be attributed directly to deleterious effects of the virus on CD4+ T cells or other particular cells. Rather, many of the functional changes that occur during the asymptomatic phase reflect a normal mode of immune resistance to chronic infection, different from the "stereotypic" immune response, whereby patterns of signals are recognized and classified and evoke selective activities. The relative stability of the virus-host relationship in this phase involves a degree of mutual adaptation. However, an excessively perturbed microenvironment is the core of unstable cellular organization in which the resistance to infection gradually deteriorates. We suggest that this is due to "overadaptation" of lymphocytes and accessory cells to the infectious agent(s). We further speculate that a key factor underlying this process is a reduced rate of replacement of CD4+ T cells, which are sequestered at the sites of infection, by fresh unprimed or memory T cells. Direct and local viral effects are amplified and propagated by "affected" cells, which are not necessarily infected. The collective profile of gene expression in various types of affected cells might adequately reflect tissue organization and the overall functional status of the immune system and thus could serve as a guide to therapy. This would require collection of a more extensive array of immunologic data than is now gathered, and novel approaches to analyzing such data.

Acquired Immunodeficiency Syndrome↗

PubMed2006

Hyperbaric oxygen therapy for malignancy: a review.

One unique feature of tumors is the presence of hypoxic regions, which occur predominantly at the tumor center. Hypoxia has a major impact on various aspects of tumor cell function and proliferation. Hypoxic tumor cells are relatively insensitive to conventional therapy owing to cellular adaptations effected by the hypoxic microenvironment. Recent efforts have aimed to alter the hypoxic state and to reverse these adaptations to improve treatment outcome. One way to increase tumor oxygen tensions is by hyperbaric oxygen (HBO) therapy. HBO therapy can influence the tumor microenvironment at several levels. It can alter tumor hypoxia, a potent stimulus that drives angiogenesis. Hyperoxia as a result of HBO also produces reactive oxygen species, which can damage tumors by inducing excessive oxidative stress. This review outlines the importance of oxygen to tumors and the mechanisms by which tumors survive under hypoxic conditions. It also presents data from both experimental and clinical studies for the effect of HBO on malignancy.

Apoptosis↗

PubMed1990

Gamma-irradiation response of cocultivated bone marrow stromal cell lines of differing intrinsic radiosensitivity.

There is evidence for differences in the gamma-irradiation response of different cellular lineages within the bone marrow microenvironment. We previously reported that heterogeneity is demonstrable in the gamma-irradiation response of five clonal stromal cell lines, derived from one human bone marrow specimen, despite morphological, histochemical, cytogenetic, and functional similarity. In the present study we tested whether one stromal cell line could affect the intrinsic radiosensitivity of another. Two clonal stromal cell lines, which display distinct gamma-irradiation responses relative to dose rate were used: KM 101, which shows the same radiosensitivity at a low dose rate of 5 cGy/min (LDR) and a high dose rate of 120 cGy/min (HDR) and KM 104 which shows significant gamma-irradiation resistance at LDR. To facilitate the study of the gamma-irradiation response of each cell line during cocultivation, we derived stable subclones of each, expressing the transfected neomycin resistance (neo-r) gene, which confers resistance to the neomycin analog: G 418. Introduction of the neo-r gene did not alter cell lines radiosensitivity. The results show that cocultivation of stromal cell lines before, during, and after gamma-irradiation induces changes in repair of radiation-induced damage, with a dominant effect of a resistant cell line at LDR. In fact, the radiation survival curves of cocultivated stromal cell lines were always characteristic of KM 104, and a dose rate effect was observed, even when KM 101 was present in large excess. Moreover, our results are consistent with preferential killing of the more radiosensitive stromal cell line: both LDR and HDR Do values of the neo-r KM 101, cocultivated with the parent KM 104 for 24 hr before, and during gamma irradiation were significantly lower compared to the neo-r subclone irradiated alone. The LDR Do value of the neo-r KM 104 cocultivated for 24 hr before, and during gamma irradiation with excess of parent KM 101, was significantly higher, compared to the neo-r cells irradiated alone.

Bone Marrow↗

PubMed1992

Cell interaction molecules and cytokines which participate in B lymphopoiesis.

A molecular and cellular definition of the bone marrow microenvironment is rapidly contributing to our understanding of lymphohaemopoiesis. While lineage specific genes and their protein products are being identified, information is accumulating about mechanisms which may regulate their expression. Stimulation of B lymphocyte precursor replication, and other discrete functions, are being attributed to cytokines such as interleukin 7 (IL-7). The activity of these factors may be controlled at the level of synthesis, local concentration and interaction with extracellular matrix. Extremely small amounts of IL-7 are made by stromal cells, which are themselves being thoroughly studied as cloned cell lines. This in vitro characterization suggests that stromal cells can make at least 12 cytokines, that they can respond to some of those cytokines themselves, and that they retain differentiation potential. Several molecules have been identified which are probably required for recognition between cells in marrow. It is noteworthy that they belong to several previously described families of adhesion molecules and none is unique to that tissue. VCAM-1 is constitutively expressed on stromal cells in marrow and can be recognized by pre-B cells which bear the integrin VLA-4. The same pair of molecules is probably responsible for extravasation of leukocytes in other tissues during inflammation. Cell adhesion molecules are likely to work in a carefully coordinated and cooperative fashion. Their activity can be controlled by expression or, in some cases, modulated after display on the cell surface. For example, while most haemopoietic cells bear CD44, only certain cells utilize it for recognition of the ligand hyaluronate. The affinity for hyaluronate can be experimentally regulated and depends on the cytoplasmic domain of CD44. This capability for dynamic change may be important for transient interactions between cells, permitting movement of maturing precursors within and from marrow.

Animals↗

PubMed2004

Estrogen receptor beta expression and apoptosis of spermatocytes of mice overexpressing a rat androgen-binding protein transgene.

Progression of the first meiotic division in male germ cells is regulated by a variety of factors, including androgens and possibly estrogens. When this regulation fails, meiosis is arrested and primary spermatocytes degenerate by apoptosis. Earlier studies showed that overexpression of rat androgen-binding protein (ABP) in the testis of transgenic mice results in a partial meiotic arrest and apoptosis of pachytene spermatocytes. In view of the recent localization of estrogen receptor beta (ERbeta) in primary spermatocytes and data suggesting the ability of ERbeta to repress cellular proliferation, we tested the hypothesis that variations in the testicular steroid microenvironment caused by excess ABP produce changes in ERbeta expression in this cellular type that could be associated to the meiotic arrest and, eventually, to the induction of germ cell apoptosis observed in the ABP transgenic mice. Increased levels of ERbeta mRNA and protein were demonstrated in the testis of rat ABP transgenic mice compared with nontransgenic littermates by reverse transcriptase-polymerase chain reaction (RT-PCR) experiments, Northern blotting, and Western Blotting. The major differences were found when isolated germ cells of transgenic and nontransgenic littermates were analyzed by RT-PCR. In keeping with this finding, ERbeta was strongly immunolabeled in pachytene spermatocytes of rat ABP transgenic mice and localized in tubular stages in which TUNEL labeling was maximal. Confocal microscopy analysis of a fluorescent TUNEL assay and ERbeta immunohistochemistry revealed that degenerating pachytene spermatocytes overexpressed ERbeta. The present results are consistent with the interpretation that ERbeta is associated with the events that regulate negatively the progression of meiosis or that lead to spermatocyte apoptosis.

Androgen-Binding Protein↗

PubMed2006

Bone biology and the pathogenesis of osteoporosis.

Much is now known about skeletal biology and the changes that take place during diseases. Skeletal development is programmed by the sequential activation of specific genetic pathways that culminate in the production of the adult skeleton, which is light but strong. Systemic hormones including parathyroid hormone, vitamin D metabolites, and calcitonin regulate blood calcium levels and contribute to the overall calcium economy of the body. Many other hormones have subtle but important effects on skeletal behaviour and its modelling and remodelling activity. At a local level, the integration of cellular differentiation and function within the microenvironment of bone is under the influence of a large number of cytokines and growth factors. Osteoporosis is a very common disorder and is a result of perturbation in these regulatory mechanisms. Much has been learnt in recent years about the many pathogenic processes that contribute to bone loss and fragility. Several drug treatments are now available to prevent bone loss and reduce the incidence of fractures, and there are prospects for the development of further novel pharmacological interventions that may modify some of the pathogenic processes themselves. Among the newer pathways for pharmacological intervention, the calcium-sensing receptor and the receptor activator of nuclear factor kappa B ligand/receptor activator of nuclear factor kappa B/osteoprotegerin system involved in osteoblast-osteoclast interactions offer exciting opportunities.

Aging↗

PubMed2003

Tissue microenvironments within functional cortical subdivisions adjacent to focal stroke.

Stroke produces a region of complete cell death and areas of partial damage, injury, and gliosis. The spatial relationship of these regions of damage to the infarct core and within spared neuronal circuits has not been identified. A model of cortical stroke was developed within functional subsets of the somatosensory cortex. Infarct size, regions of apoptosis, oxidative DNA damage, heat shock protein induction, and subtypes of reactive gliosis were precisely mapped with the somatosensory body map, quantified, and interrelated. Three tissue microenvironments were recognized: zones of partial ischemic damage, heat shock protein induction, and distributed gliosis. These three zones involved progressively more distant cortical regions, each larger than the infarct core. The zone of partial ischemic damage represents an overlap region of apoptotic cell death, oxidative DNA damage, loss of synaptic connections, and local reactive gliosis. The zone of distributed gliosis occupies distinct functional areas of the somatosensory cortex. The tissue reorganization induced by stroke is much larger than the stroke site itself. Adjacent tissue microenvironments are sites of distinct reactive cellular signaling and may serve as a link between the processes of acute cell death and delayed neuronal plasticity after focal stroke.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2005

Regulation of YKL-40 expression during genotoxic or microenvironmental stress in human glioblastoma cells.

YKL-40 is a 40 kDa secreted glycoprotein belonging to the family of 'mammalian chitinase-like proteins', but without chitinase activity. YKL-40 has a proliferative effect on fibroblasts, chondrocytes and synoviocytes, and chemotactic effect on endothelium and vascular smooth muscle cells. Elevated YKL-40 levels are found in serum of patients with diseases characterized by inflammation, fibrosis and tissue remodeling. Several studies have reported that high serum YKL-40 levels in patients with cancer are associated with poor prognosis. YKL-40 expression is strongly elevated in serum and biopsy material from glioblastomas patients. We investigated the expression of YKL-40 in three human malignant glioma cell lines exposed to different types of stress. Whereas a polymerase chain reaction transcript was detectable in all three cell lines, only U87 produced measurable amounts of YKL-40 protein. In U87, hypoxia and ionizing radiation induced a significant increase in YKL-40 after 24-48 h. The hypoxic induction of YKL-40 was independent of HIF1. Etoposide, ceramide, serum depletion and confluence all led to elevated YKL-40. Inhibition of p53 augmented the YKL-40 expression indicating that YKL-40 is attenuated by p53. In contrast, both basic fibroblast growth factor and tumor necrosing factor-alpha repressed YKL-40. These are the first data on regulation of YKL-40 in cancer cells. Diverse types of stress resulted in YKL-40 elevation, which strongly supports an involvement of YKL-40 in the malignant phenotype as a cellular survival factor in an adverse microenvironment.

Adipokines↗

PubMed2004

Differential damage and recovery of human mesenchymal stem cells after exposure to chemotherapeutic agents.

Mesenchymal stem cells (MSCs) are an important cellular component of the bone marrow microenvironment for supporting haemopoiesis. However, their response to high-dose chemotherapy remains unknown. We assessed the acute direct effects of individual chemotherapeutic agents on human MSCs (hMSCs). Using an in vitro culture system, the chemosensitivity of hMSCs was determined by XTT (2,3-bis(2-methoxy-4-nitro-5-sulphophenyl)-5-[(phenylamino) carbonyl]-2H-tetrazolium hydroxide) assay in comparison with that of NB-4 cells, a leukaemic cell line, and normal peripheral blood mononuclear cells. The recovery of cell numbers following exposure to chemotherapeutic agents and chemotherapy-induced apoptosis of hMSCs were evaluated. Human MSCs were resistant to chemotherapeutic agents commonly used in bone marrow transplantation (BMT) (i.e. busulphan, cyclophosphamide and methotrexate). However, they were relatively sensitive to a panel of cytotoxic agents, such as paclitaxel, vincristine, etoposide and cytarabine. Furthermore, different recovery patterns were noted. There was sustained suppression in hMSCs following 3 d exposure to paclitaxel, cytarabine and etoposide. In contrast, significant recovery was seen in hMSCs treated with dexamethasone and vincristine respectively. Human MSCs have different patterns of response to a panel of chemotherapeutic agents commonly used in BMT or cancer therapy. Understanding this variation is important in optimizing conditioning regimens for BMT.

Antineoplastic Agents↗

PubMed1989

Human hemopoietic growth factors.

Hematopoiesis is regulated by a complex network of soluble stimulators and inhibitors, as well as by cellular interactions in the bone marrow microenvironment. Progress in molecular biology and protein biochemistry has provided a number of hemopoietic growth factors that are now available in large quantities for in vitro and in vivo studies. Several of them seem to hold great promise for patients suffering from insufficient hematopoiesis of various causes. This review focuses on new developments in the understanding of hemopoietic growth factors activity, and on recent clinical data.

Colony-Stimulating Factors↗

PubMed1984

LPS stimulation of complement (C3) synthesis by a human monocyte cell line.

The human monocyte-like cell line, U937, was utilized as a model system to assess the influence of lipopolysaccharides (LPS) from Escherichia coli and other immunomodulatory agents on the biosynthesis of complement component C3 by monocytoid cells. The amount of C3 accumulated in the medium of cultured cells was measured by an enzyme-linked immunoabsorbent assay (ELISA). In the presence of LPS (0.01 and 0.10 microgram/ml) C3 production by U937 cells was increased by 2- and 5-fold, respectively. C3 production was also increased in the presence of lymphokine-containing supernatants obtained from human peripheral blood mononuclear cells after their stimulation with concanavalin A-sepharose. Human gamma-interferon (50-500 units/ml) stimulated C3 production by U937 cells. Stimulation of C3 production by LPS or mononuclear cell supernatants was blocked by cycloheximide. LPS (0.10 and 1.0 microgram/ml) also stimulated PGE2 production by U937 cells but failed to increase PGE2 at the lowest concentration (0.01 micrograms/ml) shown to increase C3 biosynthesis. Although exogenous PGE1 (10(-7) and 10(-6) M) promoted a small increase in C3 production, the effect of LPS was not decreased by a concentration of indomethacin (10(-6) M) that inhibited biosynthesis of PGE2. Therefore, LPS-induced C3 synthesis is not mediated by an increase in PGE2 in U937 cells. In summary, these observations suggest that C3 biosynthesis by monocytes/macrophages can be modulated by mediators of cellular immune responses found in the microenvironment of a localized inflammatory reaction.

Alprostadil↗

PubMed1996

Differentiation and integrity of cardiac muscle cells are impaired in the absence of beta 1 integrin.

Cellular interactions with substrata of the microenvironment are one of the major mechanisms for differentiation and morphogenesis. Many of these interactions are mediated via the beta 1 integrin subfamily of cell surface receptors, which are believed to transduce signals upon cell adhesion. We have used beta 1 integrin-deficient embryonic stem cells to test their ability to differentiate into cardiac muscle cells. We show here by several approaches that beta 1 integrin is important for normal cardiogenesis. First, the in vitro differentiation of beta 1 integrin-deficient embryonic stem cells into cardiac muscle cells is retarded. This is demonstrated by the delayed expression of cardiac muscle-specific genes and action potentials. Second, the specification of cardiac precursor cells into pacemaker-, atrial- and ventricular-like cells is significantly impaired in beta 1 integrin-deficient cells. The occurrence of atrial- and ventricular-like cells is reduced and transient. Only cells exhibiting peacemaker-like action potentials of high frequency and arrhythmias survive. Third, the sarcomeric architecture is incomplete and disarranged in the absence of beta 1 integrin. Fourth, beta 1-deficient embryonic stem cells can contribute to the developing heart in chimaeric mice but many areas with beta 1-null cells contain cell debris. The number of beta 1-null cells decrease from prenatal to postnatal stages and is lost completely in 6-month-old hearts. Thus, we conclude that interactions with the extracellular matrix via beta 1 integrin is necessary for differentiation and the maintenance of a specialized phenotype of cardiac muscle cells.

Animals↗

PubMed2003

Myelodysplastic syndromes. Contemporary biologic concepts and emerging diagnostic approaches.

The myelodysplastic syndromes (MDS) are an enigmatic group of clonal hematopoietic stem cell disorders associated with significant morbidity and mortality. Typically, MDS evolves from an early phase of accelerated apoptosis resulting in ineffective hematopoiesis to a later phase of increasing proliferation with maturation arrest. Afflicted patients experience a deteriorating course characterized by peripheral cytopenia(s) with consequent infection and hemorrhage and, in some cases, progression to acute leukemia. The classification of MDS has been a matter of some controversy, perhaps allied to our largely unsatisfactory insights into the pathobiology of the disease. Recently, however, new concepts have emerged to explain the etiology and pathogenesis of MDS that invoke a model for step-wise genetic progression with modulation by the immune system and the marrow microenvironment. From these insights into its cellular and molecular pathogenesis have emerged new strategies for both diagnosis and treatment. With the implementation of these strategies, it is anticipated that a more rational and objective approach to the diagnosis and classification of MDS may be achieved, affording the use of more effective targeted therapy.

Humans↗

PubMed1998

The growth inhibitory role and potential clinical value of macrophage inflammatory protein 1 alpha in myeloid leukaemias.

The control of primitive haemopoietic progenitor cell proliferation in vitro can be achieved with combinations of growth stimulatory cytokines. Acting in apparent opposition to these growth stimulators are growth inhibitory substances, including prostaglandins, cytokines and chemokines which bind to specific cognate cell surface receptors and promote signal transduction events that interfere with cellular proliferation. Within the bone marrow microenvironment, significant quantities of both growth inhibitors and growth promoters can be detected. The ratio of their concentrations within microenvironmental niches of the marrow may regulate primitive blood cell production. The potential exists, therefore, for the disregulation of haemopoiesis via the disruption of the balance between positive and negative regulators of haemopoietic progenitor proliferation. In one particular disease, chronic myeloid leukaemia (CML), there is a lack of response of leukaemic cells to the chemokine growth inhibitor, Macrophage Inflammatory Protein-1alpha (MIP-1alpha). The role of MIP-1alpha in regulation of haemopoiesis, the response of CML progenitor cells and other myeloid leukaemic cells to this chemokine, and the reasons for lack of response to MIP-1alpha in leukaemic cells are reviewed.

Chemokine CCL3↗