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PubMed1997

Immune response decisions at the single cell level.

Helper T cells regulate the progressive differentiation of antigen-specific B cells in complex and dynamic microenvironments in vivo. In this review, antigen-driven B-cell differentiation will be discussed in three phases: pre-germinal center, germinal center and post-germinal center. Each phase of the response appears to have unique cellular starting points, specialized regional microenvironments and its own set of controls and cellular outcomes. Decisions made by individual lymphocytes at each of these phases determines the shape of protective immunity in vivo.

Animals↗

PubMed2025

3D Cell Culture Models as a Platform for Studying Tumor Progression, Testing Treatment Responses, and Discovering Biomarkers.

In this chapter, we present a detailed protocol for establishing a three-dimensional (3D) multicellular tumor spheroids (MCTSs) model to simulate the tumor microenvironment (ME) associated with metabolic dysfunction-associated steatotic liver disease (MASLD) for the study of hepatocellular carcinoma (HCC) and colorectal cancer (CRC) cell aggressiveness, growth, and metastasis potential. The MASLD microenvironment (MASLD-ME) is recreated by embedding hepatic stellate cells in a collagen I matrix within a Boyden chamber system. The metabolic medium mimics MASLD conditions, enriched with high glucose, fructose, insulin, and fatty acids, to simulate metabolic stresses associated with the disease.In the protocol, cancer cells are loaded in the upper compartment to analyze their migration toward the MASLD-ME, thereby facilitating studies on cancer cell invasiveness and metastatic capacity. This method offers an adaptable, reproducible model to research disease progression and investigate therapeutic interventions, contributing to preclinical research on MASLD-related liver cancer pathophysiology and potential drug responses.

Humans↗

PubMed1994

Discovery of novel hematopoietic cell adhesion molecules from human bone marrow stromal cell membrane protein extracts by a new cell-blotting technique.

In an attempt to define the role of cell adhesion molecules (CAMs) within the bone marrow (BM) microenvironment in normal hematopoiesis and in leukemia development, a novel cell-blotting technique that involved cell adhesion to protein bands after separation by lithium dodecyl sulfate-polyacrylamide gel electrophoresis (LDS-PAGE) and blotting onto polyvinylidene difluoride (PVDF) membrane has been developed. Human BM stromal cell membrane fractions have been prepared from Dexter-type cultures after cell lysis by sonification and differential centrifugations of the sonification contents. The 20,000 g pellets representing membrane fractions have been solubilized by 2% Triton X-100, 0.575% LDS, and 8 mol/L urea in sequential order. The protein extracts are fractionated by LDS-PAGE and screened for CAMs by the new cell-blotting technique. This led to identification of nine protein bands in lanes containing LDS extracts showing adhesion of KG1a (CD34+ progenitor myeloid) cells. Evidence that the BM proteins exhibiting KG1a cell adhesion are novel CAMs is based on the observations that these proteins, in comparison with known CAMs, specifically VCAM-1, CD54, and CD44, show (1) contrasting detergent-solubility properties, (2) different temperature requirement for mediating cell adhesion function, and (3) markedly distinct electrophoretic mobilities. The various cell types tested, notably KG1a, NALM-6, WIL-2, Ramos, HS-Sultan, K562, JY B lymphoblastoid cells, and T lymphoblasts, showed distinctive patterns of binding to different subsets of BM CAMs. These results demonstrate a new approach to studies of molecular mechanisms that may determine specificity of hematopoietic cellular localization within BM microenvironment and may play an important role in controlling hematopoiesis.

Bone Marrow↗

PubMed1995

The thymic nurse cell complex: an in vitro model for extracellular matrix-mediated intrathymic T cell migration.

The thymus is a primary lymphoid organ in which bone marrow-derived T cell precursors undergo a complex maturation process in the context of the thymic microenvironment, represented by non-lymphoid cells and extracellular matrix (ECM) components. The thymic epithelial cells are the major cellular component of the thymic microenvironment, and influence different aspects of thymocyte differentiation, via cell-cell interactions and secretions of soluble factors, such as thymic hormones. The thymic nurse cell (TNC) complexes are multicellular lymphoepithelial structures formed by one thymic epithelial cell harboring 2-200 thymocytes, primarily bearing the CD4/CD8 double-positive phenotype. TNCs probably create a special microenvironment for thymocyte differentiation and/or proliferation, with thymocytes being exposed to major histocompatibility complex (MHC) antigens and thymic hormones. Such differentiation parallels cell migration into and out of the complex. We showed the expression of ECM components and respective receptors by TNCs, and that interactions between the epithelial component of TNC and TNC-lymphocytes can be modulated by ECM components and respective receptors. Moreover, we demonstrated that intrinsic as well as extrinsic biological circuits can be involved in the control of such ECM-mediated thymic epithelial cell (TEC)/thymocyte interactions. For example, interferon-gamma can biphasically modulate the expression of ECM ligands and receptors by TEC, which results in corresponding modulation of their ability to interact with TNC-thymocytes. Additionally, hormones such as triiodothyronine, prolactin and growth hormone can influence the degree of these lymphocyte/epithelial cell adhesive interactions. Lastly, we recently furnished evidence for a de-adhesive mechanism within TNC apparently mediated by galectin 3 (an endogenous soluble beta-galactoside-binding lectin).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2026

Matrix Mechanics Governs Mechano-Metabolic Adaptation across Cancer Grades in Bladder Spheroids.

Extracellular matrix (ECM) mechanics is pivotal regulators of tumor progression, yet how viscoelasticity and matrix architecture converge to shape metabolic and invasive adaptation remains insufficiently defined. We postulate that mechanical stimuli from the ECM induce coordinated changes in adhesive and metabolic pathways, and that the nature of this independent mechano-metabolic pathway is conserved across benign, low-invasive, and high-invasive bladder cancer phenotypes. Therefore, we engineered collagen-hyaluronan hydrogels with tunable stiffness to recapitulate soft and rigid tumor microenvironments and profiled bladder cancer spheroids representing benign, low-invasive, and highly invasive states. Integrating hydraulic force spectroscopy, rheology, and molecular phenotyping, we show that matrix stiffening differentially reprograms spheroid architecture, motility, and adhesion- and metabolism-related gene expression. Spheroid behavior emerged from the interplay between intrinsic mechanical properties, matrix rheology, and molecular adaptation. HCV29 spheroids formed rigid, compact structures, relying on cell-matrix adhesion rather than metabolic or proteolytic remodeling. HT1376 spheroids activated glycolysis (HK2) and MMP-2-dependent ECM remodeling in soft matrices, but remained largely nonmigratory, indicating decoupling of invasive priming from motility. T24 spheroids were soft, deformable, and highly migratory in compliant matrices, integrating metabolic reprogramming, adhesion remodeling (E-/N-cadherin, SDC4), and radial collagen fiber alignment to drive invasion. Notably, canonical FAK/AKT/mTOR signaling was absent across all spheroids, while pS6 ribosomal protein and ILK indicated noncanonical, SDC4/integrin-ILK-dependent mechanotransduction supporting cytoskeletal dynamics, metabolism, and ECM remodeling. Collagen organization further differed across spheroid types, with dense, radially aligned fibers in HT1376, intermediate architecture in HCV29, and loose, disorganized networks in T24, closely matching their distinct migratory behaviors and cell-ECM interactions. These findings reveal stage-specific mechanometabolic strategies in bladder cancer, demonstrating how ECM mechanics and architecture jointly guide invasion, metabolic adaptation, and local immune modulation, including the regulation of immune cell infiltration and tumor immune evasion.

Humans↗

PubMed1985

Production of plasminogen activator by migrating cephalic neural crest cells.

Neural crest cells migrate extensively during embryonic development and differentiate into a wide variety of cell types. Our working hypothesis is that during migration, embryonic cells secrete proteases which modify local microenvironments, thereby facilitating directed cellular movements. In this communication, we report studies on the migration of cephalic neural crest cells in the avian embryo. We demonstrate that these cells produce high levels of the serine protease, plasminogen activator (PA), at the time of their initial migration from the neural tube and during their migration to and colonization of the developing head and neck.

Animals↗

PubMed1987

Human mononuclear cell in vitro activation in microgravity and post-spaceflight.

The results of postflight and inflight human in vitro lymphocyte experiments have been reviewed. The cumulative data indicate that mitogen-stimulated T-cell proliferation is blunted following short-duration missions. Since similar responses may also be obtained following exposure to non-spaceflight stressors (hypoxia and academic stress), it is unclear if microgravity per se aggravates this response. Our studies indicate that stress-induced impaired PHA- and PWM-stimulated activation can be detected within the first 24 hours in culture at the level of protein synthesis. While the mechanism for neuroendocrine-mediated blunted mitogen stimulated T cell proliferation has not been elucidated, it is not aggravated by autologous plasma and does not require changes in mononuclear cell subpopulations. While prior studies indicate lymphocyte activation is influenced by altering G forces on in vitro cultures, impaired cellular interactions or suboptimal microenvironments related to reduced cell densities in microgravity may contribute to the greatly impaired mitogen stimulated proliferation responses observed on Spacelab flights. It will be necessary to perform lymphocyte functional assays on crewmembers during spaceflight to determine to contribution of microgravity per se on altered human immune competence.

Female↗

PubMed1994

Evidence against the "oxygen-in-the-track" hypothesis as an explanation for the radiobiological low oxygen enhancement ratio at high linear energy transfer radiation.

Oxygen sensitizes cells toward the effect of ionizing radiation. This sensitization, quantified by the oxygen enhancement ratio (OER), decreases with increasing ionization density or linear energy transfer (LET) of the radiation applied. One explanation for the decreased OER at high LET offers the "oxygen-in-the-track" hypothesis. It claims that oxygen is produced in the track of densely ionizing particles providing an oxic microenvironment around the relevant cellular target molecules, even if cells are exposed under anoxic atmospheric conditions. Experimental evidence is presented against this hypothesis. It is based on the different kinetic pattern of DNA double-strand-break rejoining observed in yeast cells exposed under oxic or anoxic conditions to 3.5 MeV alpha-particles.

DNA↗

PubMed1988

An immunohistochemical and fine-structural analysis of peptidergic hypothalamic neurosecretory axon regeneration into the leptomeninges of the rat.

Regeneration of severed hypothalamic peptidergic neurosecretory axons into the ventral pia-arachnoid was observed in rats at the light microscopic and fine-structural levels. A temporal increase occurred in the number of neurophysin-positive axons regenerating into the leptomeninges for distances up to 3.3 mm by 40 days post-lesioning. A consistent pattern of parallel, meshed and clustered axons, occurring either singly or in bundles, was present within the connective tissue, while plexus and bundles were observed in association with leptomeningeal blood vessels. Axons were characterized by preterminal and terminal dilatations. Neurosecretory granulated vesicles occurred throughout axons. The presence of microvesicles at contact points with basal lamina suggests the possibility of hormone release. Most axons were arranged as fascicles associated closely with basal lamina-bounded support cells whose thin lamellar processes wrapped single axons or fascicles of axons. We conclude, therefore, that cellular and intercellular leptomeningeal microenvironments support and sustain the growth and regeneration of transected neurosecretory axons.

Animals↗

PubMed1988

Contact-dependent inhibition of growth of normal diploid human fibroblasts by plasma membrane glycoproteins.

Homeostasis in vivo is maintained by a highly complex network of positive and negative signals. At the cellular level, this regulatory microenvironment can be divided, in a simplified fashion, into two major compartments: the humoral compartment, including compounds such as hormones, growth factors and nutrients, and the contact-environment compartment, including cell-cell and cell-matrix interactions. At least in cultures of diploid, non-transformed cells, cell-cell and cell-matrix interactions have been shown to be of major importance for the regulation of growth as well as of differentiation. Although until now the glycoprotein involved in the contact-dependent inhibition of growth has not been fully characterized, our studies give evidence for the involvement of a plasma membrane glycoprotein with an apparent molecular weight of approximately 80 kDa in the growth regulation of diploid human fibroblasts. The important characteristic of this glycoprotein is: the biologically active determinant resides in terminal, beta-glycosidically linked galactose residues on N-glycosidically linked glycans. From our studies, a receptor has to be postulated which, in addition to the galactose residues, has additional structural requirements for the specific binding of this glycoprotein, since other glycoproteins carrying terminal, beta-glycosidically linked galactose-residues are without biological activity. The postulated receptor is suggested to be defective in tumor cells, since these cells are no longer able to respond to cell-cell contacts with stopped proliferation, although they are able to inhibit growth of non-transformed cells. The inability of a tumor cell to recognize and to bind to the specific glycoprotein would result in a release from growth inhibition, leading to clonal growth of these cells. Further detailed studies on the structure and the regulation of the glycoprotein, as well as an attempt to isolate the postulated receptor, should lead to a better understanding of the complex pattern of growth regulation of normal cells.

Animals↗

PubMed2002

Analysis of thymic stromal cell populations using flow cytometry.

The complexity of the lymphostromal interplay that is essential to alphabetaT-cell development is reflected by the heterogeneity of both lymphocytes and thymic stromal cells. While panels of monoclonal antibodies have described many of the cellular components of these microenvironments, the means to quantify stromal cell subsets using flow cytometry remains poorly defined. This study refines and compares various stromal cell isolation procedures and determines the effects of various digestion enzymes on important surface molecules. Three- and four-color flow cytometry is used to correlate established and novel stromal cell markers to define thymic fibroblasts, epithelium and a unique subset of thymic endothelium that express MHC class II. This work provides a basis for the purification of thymic stromal cells for further phenotypic, functional and genetic analysis.

Animals↗

PubMed1982

Immunoperoxidase staining for involucrin: a potential diagnostic aid in cervicovaginal pathology.

Involucrin, a protein subunit of keratinocyte cross-linked envelopes, is a distinctive marker for suprabasal differentiation in stratified squamous epithelium. Immunoperoxidase staining for involucrin was used to evaluate paraffin sections of tissue obtained by colposcopically directed biopsies of infectious, metaplastic, and dysplastic lesions of the cervix and vagina. Areas of normal squamous epithelium, papillary and flat condyloma acuminatum, and mature and immature squamous metaplasia showed positive staining in 99 per cent of samples lacking significant inflammation and in 60 per cent of those with moderate or severe inflammation. In contrast, only 19 per cent of the squamous cell dysplasias, even those without much inflammation, showed positive staining, and no area with moderate or severe inflammation showed positive staining. These findings indicate that expression of involucrin is modulated by cellular pathologic features and microenvironment. We suggest that immunoperoxidase staining for involucrin may be useful in distinguishing mild dysplasia from immature metaplasia and flat condyloma in some biopsy specimens in which routine histologic examination yields an indeterminate diagnosis.

Carcinoma, Squamous Cell↗

PubMed1997

Premature thymic involution, observed at the ultrastructural level, in two lineages of human-SOD-1 transgenic mice.

The human Cu/Zn superoxide dismutase (hSOD-1) gene, catalyses the dismutation of O2 to H2O2 and O2. It is located on chromosome 21 in q22.1 and is overexpressed in Down's syndrome (DS) patients. These patients present various abnormalities including mental retardation, congenital heart disease, immunological deficits and premature aging. In order to explore the potential role of SOD-1 overexpression in DS, we have generated two lineages of transgenic mice for the hSOD-1 gene and studied, at the ultrastructural level, the effect of hSOD-1 overexpression on the thymic microenvironment. Modification of the cellular architecture and morphology associated with a lipidic invasion, signs of a premature involution of the thymus, were observed in both lineages. A rupture of the filamentous network in the extracellular and probably also in the intracellular matrix was first observed. These results correlate the thymic alterations visualized in light microscopy, on the thymus from DS patients, and raise the question of the relationship between the SOD-1 overexpression and the different morphological alterations associated with the premature thymic involution observed in SOD-1 transgenic mice. They suggest that thymic and immunological impairments present in DS patients may be related to the SOD-1 gene dosage effect.

Aging↗

PubMed2000

In vitro inhibition of murine hematopoietic progenitors and stromal cells by vinorelbine.

Hematopoietic progenitor colony assays were used to establish the effects of the vinca alkaloid vinorelbine (VRB) on murine bone marrow. The in vitro growth of colony-forming units-granulocyte/macrophage (CFU-GM), burst forming units-erythroid (BFU-E) and colony-forming units-mix (CFU-mix) was dose-dependently inhibited by VRB. The highest dose assayed (0.02 microg/ml) suppressed all of the different progenitor cells by 100%. A comparison of the dose-response curves showed that CFU-GM, BFU-E, and CFU-mix exhibited similar-patterns of sensitivity to the cytotoxic action of VRB. Long-term bone marrow cultures have provided a valuable in vitro model for studying the role of the microenvironment of bone marrow. Cellularity of stromal layers was reduced with increasing doses of VRB. The appearance of these layers was altered minimally with the lowest dose used; a gradual loss of cellularity was seen in cultures exposed to 0.05 and 0.075 microg/ml; and a marked loss at the dose of 0.1 microg/ml. Our results show that VRB has an important effect on hematopoietic progenitors at the highest dose tested, while the stromal cells were not affected at a similar dose (0.025 microg/ml), suggesting that the stroma is more resistant to this drug.

Animals↗

PubMed2002

Prostate tumor-stroma interaction: molecular mechanisms and opportunities for therapeutic targeting.

Maintenance of cell and tissue homeostasis is dependent upon the dynamic balance of cell proliferation, differentiation, and apoptosis through interactions between cells and their microenvironment. The unique prostatic cellular phenotypes are induced and maintained by interaction between epithelium and adjacent stroma through intimate intercellular signaling pathways. In this article, we summarize current advances in the tumor-stroma interaction and its biologic and therapeutic implications. We specifically emphasize current studies of the possible factors driving the "vicious cycle" between stroma and emerging prostate tumor epithelial cells that may be responsible for carcinogenesis and metastasis to bone. Stroma responds both genotypically and phenotypically to tumor epithelium upon co-culture under 3-D conditions. Likewise, the emerging carcinoma responds to stromal signals that drive progression to malignancy. A vicious cycle mediated by soluble and insoluble molecules secreted by tumor cells and stroma appear be the critical factors supporting and sustaining tumor colonization in bone. Co-targeting tumor and stroma with therapeutic agents has yielded promising results both in pre-clinical models of prostate cancer and bony metastasis and in clinical trials of patients treated with a dual tumor and stroma targeting strategies. In conclusion, understanding and targeting the interaction of the tumor and its stromal microenvironmant may improve the prognosis, reduce the suffering and increase the survival of patients with advanced cancer metastasis.

Cell Communication↗

PubMed1993

Cellular regulatory mechanisms that may underlie the effects of corticosteroids on bone.

The overall effects of corticosteroids on the skeleton are dependent on many factors including dose, duration of exposure to the steroid, steroid type and species. Some effects are indirect and are brought about by changes in, for example, parathyroid hormone secretion and intestinal calcium absorption, while others may result from cellular responses within the microenvironment of bone itself. Explants of trabecular bone are commonly used to study glucocorticoid effects in vitro, though it is often difficult to be certain that in vitro results directly reflect in vivo activity. Corticosteroids are dual inhibitors of cyclo-oxygenase and lipo-oxygenase, and may exert effects via inhibition of eicosanoid synthesis. They can also inhibit synthesis of cytokines, such as interleukin-1, which stimulate bone resorption and remodelling, by monocytes and macrophages. The production of cytokines and growth factors by bone cells themselves and the expression of their receptors may also be influenced by corticosteroids. Examples of corticosteroid-induced inhibition of synthesis include tumour necrosis factor and interleukin-6, and such effects may be important in explaining therapeutic actions of corticosteroids (e.g. in myeloma). Although it is not yet clear why different glucocorticoids have different effects, a number of factors determine the overall effect of a steroid. These include steroid metabolism and tissue distribution, selective effects on cytokine production, and tissue differences in gene transcription.

Arthritis, Rheumatoid↗

PubMedDate not supplied

Control of the thymic microenvironment by growth hormone/insulin-like growth factor-I-mediated circuits.

The thymus gland is a central lymphoid organ in which bone marrow-derived T cell precursors undergo maturation, eventually leading to the migration of positively selected thymocytes to the T-dependent areas of peripheral lymphoid organs. This process occurs under the influence of the thymic microenvironment, by means of secretory polypeptides and cell-cell contacts. The thymic microenvironment is a tridimensional cellular network composed of epithelial cells (its major component), macrophages, dendritic cells, fibroblasts and extracellular matrix elements. The epithelial reticulum is a heterogeneous tissue, in which a particular lymphoepithelial structure has been isolated in vitro: the thymic nurse cell complex, which possibly creates particular microenvironmental conditions for thymocyte differentiation. Additionally, thymic nurse cells are useful tools to study mechanisms involved in intrathymic T cell migration, including neuroendocrine influences. Previous data showed that thymic hormonal function can be modulated by hormones and neuropeptides, including growth hormone. Interestingly, GH acts pleiotropically on the thymic epithelium increasing cell growth and expression of extracellular matrix ligands and receptors, the latter resulting in an enhancement of thymocyte adhesion to the epithelial cells and thymocyte release from thymic nurse cells. The role of GH on thymus development is further stressed by the findings obtained with GH-deficient dwarf mice. Besides the precocious decline in serum thymulin found in these animals, a progressive thymic hypoplasia occurs, with decreased numbers of CD4+CD8+thymocytes, both defects being largely restored by long-term GH treatment. The effects of GH in the thymus are apparently mediated by IGF-1. Enhancement of thymulin secretion induced by GH, as well as the stimulation of thymocyte adhesion to thymic epithelial cells can be prevented in vitro by treatment with antibodies for IGF-I or IGF-I receptor. Moreover, in both systems IGF-I alone can yield similar effects. Also, the enhanced concanavalin-A mitogenic response and IL-6 production by thymocytes observed in GH-treated mice can be detected in animals treated with IGF-I. Lastly, mouse substrains selected for high or low IGF-I circulating levels exhibited differential thymus developmental patterns correlating with IGF-I levels. A further conceptual aspect concerning the GH-IGF-I-mediated control of thymus physiology is the recent demonstration of an intrathymic production of these molecules, leading to the hypothesis that, in addition to the classical endocrine pathway, GH-IGF-I-mediated paracrine and autocrine pathways may also be implicated in the control of thymus physiology. In any case, such control is exerted pleiotropically, with modulation in the expression of several genes in different cell types of the organ. In this respect, it is exciting to imagine a role of GH-IGF-I loops in shaping the intrathymically generated T cell repertoire.

Cell Differentiation↗

PubMed1996

Persistence of nontypeable Haemophilus influenzae in adenoid macrophages: a putative colonization mechanism.

That nontypeable H. influenzae (NTHI) can reside intracellularly in human adenoid tissue has been suggested by use of in situ hybridization of a fluorescein labelled 16S rRNA-targeted oligonucleotide probe (FISH). Adenoid tissues from 43 children operated on in a clinically infection-free interval were investigated. FISH revealed H. influenzae in macrophage-like cells, located subepithelially in the crypts in all 43 adenoids. Furthermore, H. influenzae was detected in 22/22 adenoids using immunohistochemistry with the monoclonal antibody MAHI-3 recognizing a conserved H. influenzae LPS inner-core region. FISH and staining with monoclonal antibodies against immunophenotypic markers were performed simultaneously in order to characterize the cellular interrelations in this microenvironment. The findings of widespread presence of H. influenzae in cells of which some strongly expressed the CD14 marker of the monocyte/macrophage lineage may correspond to an important aspect of the colonization mechanisms whereby NTHI persists in the nasopharynx of children.

Adenoids↗