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At least 1,423 records · Page 79Linked to original sources
PubMed2004

Effects of crosslinking degree of an acellular biological tissue on its tissue regeneration pattern.

It was reported that acellular biological tissues can provide a natural microenvironment for host cell migration and may be used as a scaffold for tissue regeneration. To reduce antigenicity, biological tissues have to be fixed with a crosslinking agent before implantation. As a tissue-engineering scaffold, it is speculated that the crosslinking degree of an acellular tissue may affect its tissue regeneration pattern. In the study, a cell extraction process was employed to remove the cellular components from bovine pericardia. The acellular tissues then were fixed with genipin at various known concentrations to obtain varying degrees of crosslinking. It was shown in the in vitro degradation study that after fixing with genipin, the resistance against enzymatic degradation of the acellular tissue increased significantly with increasing its crosslinking degree. In the in vivo subcutaneous study, it was found that cells (inflammatory cells, fibroblasts, endothelial cells, and red blood cells) were able to infiltrate into acellular tissues. Generally, the depth of cell infiltration into the acellular tissue decreased with increasing its crosslinking degree. Infiltration of inflammatory cells was accompanied by degradation of the acellular tissue. Due to early degradation, no tissue regeneration was observed within fresh (without crosslinking) and the 30%-degree-crosslinking acellular tissues. This is because the scaffolds provided by these two samples were already completely degraded before the infiltrated cells began to secrete their own extracellular matrix. In contrast, tissue regeneration (fibroblasts, neo-collagen fibrils, and neo-capillaries) was observed for the 60%- and 95%-degree-crosslinking acellular tissues by the histological examination, immunohistological staining, transmission electron microscopy, and denaturation temperature measurement. The 95%-degree-crosslinking acellular tissue was more resistant against enzymatic degradation than its 60%-degree-crosslinking counterpart. Consequently, tissue regeneration was limited in the outer layer of the 95%-degree-crosslinking acellular tissue throughout the entire course of the study (1-year postoperatively), while tissue regeneration was observed within the entire sample for the 60%-degree-crosslinking acellular tissue. In conclusion, the crosslinking degree determines the degradation rate of the acellular tissue and its tissue regeneration pattern.

Animals↗
PubMed2007

In vivo tumor targeting and radionuclide imaging with self-assembled nanoparticles: mechanisms, key factors, and their implications.

The development of more selective delivery systems for cancer diagnosis and chemotherapy is one of the most important goals of current anticancer research. The purpose of this study is to evaluate various self-assembled nanoparticles as candidates to shuttle radionuclide and/or drugs into tumors and to investigate the mechanisms underlying the tumor targeting with self-assembled nanoparticles. By combining different hydrophobic moieties and hydrophilic polymer backbones, various self-assembled nanoparticles were prepared, and their in vivo distributions in tumor-bearing mice were studied by radionuclide imaging. One type of nanoparticles (fluorescein isothiocyanate-conjugated glycol chitosan (FGC) nanoparticles) exhibited highly selective tumoral localization. Scintigraphic images obtained 1 day after the intravenous injection of FGC nanoparticles clearly delineated the tumor against adjacent tissues. The mechanisms underlying the tumor targeting with self-assembled nanoparticles were investigated in terms of the physicochemical properties of nanoparticles and tumor microenvironments. FGC nanoparticles were preferentially localized in perivascular regions, implying their extravasation to tumors through the hyperpermeable tumor vasculature. The magnitude and pattern of tumoral distribution of self-assembled nanoparticles were influenced by several key factors--(i) in vivo colloidal stability: nanoparticles should maintain their intact nanostructures in vivo for a long period of time, (ii) particle size, (iii) intracellular uptake of nanoparticle: fast cellular uptake greatly facilitates the tumor targeting, (iv) tumor angiogenesis: pathological angiogenesis permits access of nanoparticles to tumors. We believe that this work can provide insight for the engineering of nanoparticles and be extended to cancer therapy and diagnosis, so as to deliver multiple therapeutic agents and imaging probes at high local concentrations.

Animals↗
PubMed1999

Membrane ion channels as physiological targets for local Ca2+ signalling.

Ionized calcium plays a central role as a second messenger in a number of physiologically important processes determining smooth muscle function. To regulate a wide range of cellular activities the mechanisms of subcellular calcium signalling should be very diverse. Recent progress in development of visible light-excitable fluorescent dyes with high affinity for Ca2+ (such as oregon green 488 BAPTA indicators, fluo-3 and fura red) and confocal laser scanning microscopy provides an opportunity for direct visualization of subcellular Ca2+ signalling and reveals that many cell function are regulated by the microenvironment within small regions of the cytoplasm ('local control' concept). Here confocal imaging is used to measure and locate changes in [Ca2+]i on a subcellular level in response to receptor stimulation in visceral myocytes. We show that stimulation of muscarinic receptors in ileal myocytes with carbachol leading to activation of inositol 1,4,5-trisphosphate receptors (IP3Rs) accelerates the frequency of spontaneous calcium sparks (discharged via ryanodine receptors, RyRs) and gives rise to periodic propagating Ca2+ waves oscillating with a frequency similar to that of carbachol-activated cationic current oscillations. Furthermore, by combining the whole-cell patch clamp technique with simultaneous confocal imaging of [Ca2+]i in voltage-clamped vascular myocytes we demonstrate that calcium sparks may lead to the opening of either Ca2+-activated Cl- channels or Ca2+-activated K+ channels, and the discharge of a spontaneous transient inward current (STIC) or a spontaneous transient outward current (STOC), respectively.

Animals↗
PubMedDate not supplied

Biomimetic collagen scaffolds for human bone cell growth and differentiation.

Type I collagen provides a structural framework for connective tissues and plays a central role in the temporal cascade of events leading to the formation of new bone from progenitors. The aim of this study was to examine the ability of the cell-binding domain of type I collagen (P-15 peptide) to promote human bone marrow stromal cell adhesion, proliferation, and differentiation on three-dimensional scaffolds. Human bone marrow stromal cells were selected, expanded, and cultured on particulate microporous ABM ("pure" hydroxyapatite) phase adsorbed with or without P-15 under basal or osteogenic conditions. Immobilized P-15 increased alkaline phosphatase activity and bone morphogenetic protein 2 (BMP-2) gene expression after 1 and 5 days as determined by real-time polymerase chain reaction. P-15 promoted human bone marrow stromal cell attachment, spreading, and alignment on ABM as well as alkaline phosphatase-specific activity in basal and osteogenic cultures. The presence of mineralized bone matrix, extensive cell ingrowth, and cellular bridging between three-dimensional matrices adsorbed with P-15 was confirmed by confocal microscopy, scanning electron microscopy, and alizarin red staining. Negligible cell growth was observed on ABM alone. In vivo diffusion chamber studies using MF1-nu/nu mice showed bone matrix formation and organized collagen formation after 6 weeks. These studies indicate the potential of P-15 to generate appropriate biomimetic microenvironments for osteoblasts and demonstrate the potential for the exploitation of extracellular matrix cues for osteogenesis and, ultimately, bone regeneration.

Adsorption↗
PubMed1987

A light microscopical study of isolated follicular dendritic cell-clusters in human tonsils.

In order to re-examine the cellular structure of isolated FDC-culsters in the germinal centers of human tonsils, a light microscopical analysis was made. Approximately 14 FDC-clusters were recovered from one enucleated germinal center using the enzyme digestion technique. The minimum unit of the FDC-clusters was composed of one FDC and 8 to 9 lymphocytes. Most of the FDC-clusters were representative of the microenvironment of the light zone at the germinal center in situ. Half of the engulfed centrocytes were supposed to be at the Go phase, and the others at the G1 to G2 phase. It is suspected that the helper-T cell has some relationship to the FDC microenvironment, and that the suppressor-T cell does not. Most of the CIgG-containing cells in the germinal centers were considered to have infiltrated into the interspace of the FDC microenvironment.

Adolescent↗
PubMed1991

Identification of stromal cell precursors in human bone marrow by a novel monoclonal antibody, STRO-1.

Murine IgM monoclonal antibody STRO-1 identifies a cell surface antigen expressed by stromal elements in human bone marrow (BM). STRO-1 binds to approximately 10% of BM mononuclear cells, greater than 95% of which are nucleated erythroid precursors, but does not react with committed progenitor cells (colony-forming unit granulocyte-macrophage [CFU-GM], erythroid bursts [BFU-E], and mixed colonies [CFU-Mix]). Fibroblast colony-forming cells (CFU-F) are present exclusively in the STRO-1+ population. Dual-color cell sorting using STRO-1 in combination with antibody to glycophorin A yields a population approximately 100-fold enriched in CFU-F in the STRO-1+/glycophorin A- population. When plated under long-term BM culture (LTBMC) conditions, STRO-1+ cells generate adherent cell layers containing multiple stromal cell types, including adipocytes, smooth muscle cells, and fibroblastic elements. STRO-1+ cells isolated from LTBMC at later times retain the capacity to generate adherent layers with a cellular composition identical to that of the parent cultures. The STRO-1-selected adherent layers are able to support the generation of clonogenic cells and mature hematopoietic cells from a population of CD34+ cells highly enriched in so-called long-term culture-initiating cells. We conclude that antibody STRO-1 binds to BM stromal elements with the capacity to transfer the hematopoietic microenvironment in vitro.

Adipose Tissue↗
PubMed1984

[Electron microscopic study of cellular differentiation in metastases of cancer of the large intestine in man].

A comparative ultrastructural study study of the stage and type of differentiation of cancer cells in the primary large intestine human adenocarcinoma and its metastases in the lymph nodes, ovaries, and greater omentum is described. Metastatic cells have been found to retain the features of specific differentiation and be represented by the same groups and main ultrastructural types as in the primary tumor. The main directions of cell differentiation in metastases and in the primary tumor were similar. The role of microenvironment of different organs appeared to be insignificant in the process of cell differentiation in metastases.

Adenocarcinoma↗
PubMed2026

Repair and regeneration across the lifespan: an ontogenetic perspective.

The capacity for tissue repair and regeneration undergoes a profound and progressive decline across the human lifespan, representing a fundamental driver of aging and chronic disease. This review establishes a comprehensive ontogenetic framework by mapping the continuous biological transition from the flawless, scarless regenerative plasticity of embryonic development to the irreversible fibrotic scarring and organ failure characteristic of senescence. We synthesize the hierarchical collapse of reparative networks across multiple biological scales. Importantly, this ontogenetic decline should not be interpreted as a purely degenerative trajectory but rather as a dynamic systems-level reprogramming in which evolutionary trade-offs prioritize tumor suppression, immune surveillance, and reproductive fitness over long-term regenerative fidelity. Recognizing this adaptive reallocation of biological resources reframes aging not simply as failure but as a predictable recalibration of repair hierarchies. At the molecular and cellular levels, the accumulation of genomic instability, unresolvable DNA damage, and mitochondrial dysfunction gradually overwhelms intracellular quality-control mechanisms. Concurrently, epigenetic drift and chronic, low-grade systemic inflammation ("inflammaging") dismantle the stem cell niche, driving adult stem cell exhaustion and shifting wound healing away from functional tissue replacement toward maladaptive fibrosis. Furthermore, we examine divergent, organ-specific repair trajectories. By contrasting the severe regenerative restrictions of the adult central nervous system and myocardium with the persistent, yet exhaustible, resilience of the liver, we elucidate the unique intrinsic and microenvironmental barriers that impede structural and functional recovery. Finally, we evaluate the clinical paradigm shift from passive management of age-related degeneration to active restoration of tissue integrity. By integrating systemic geroscience-which addresses the global hallmarks of aging-with targeted bioengineering and in vivo epigenetic modulation, contemporary regenerative medicine seeks to recreate permissive, youthful microenvironments. Ultimately, mastering these ontogenetic principles holds unprecedented potential to reactivate endogenous repair pathways, mitigate multi-organ collapse, and significantly extend human functional healthspan.

DNA repair↗
PubMed2003

Intestinal epithelial exosomes carry MHC class II/peptides able to inform the immune system in mice.

BACKGROUND: Intestinal epithelial cells secrete exosome-like vesicles. The aim of this study was to characterise murine intestinal epithelial exosomes and to analyse their capacity to inform the immune system in vivo in mice. METHODS: Epithelial exosomes were obtained from the murine epithelial cell line MODE K incubated in the presence or absence of interferon gamma (IFN-gamma) together with pepsin/trypsin ovalbumin hydrolysate (hOVA) to mimic luminal digestion. Exosomes isolated from MODE K conditioned media (EXO-hOVA and EXO-hOVA-IFN) were characterised by western blot, peptide mapping, and mass spectrometry. They were injected intraperitoneally to C3H/HeN mice to test their immunocompetence. RESULTS: MODE K epithelial exosomes displayed major histocompatibility complex (MHC) class I and class II (upregulated by IFN-gamma) molecules and tetraspan proteins (CD9, CD81, CD82) potentially involved in the binding to target cells. A33 antigen, an Ig-like molecule highly specific for intestinal epithelial cells, was enriched in exosomes and was also found in mice mesenteric lymph nodes, suggesting exosome migration towards the gut associated lymphoid tissues. Intraperitoneal injection of EXO-hOVA or EXO-hOVA-IFN did not induce humoral or cellular tolerance to OVA in mice. In contrast, exosomes obtained after incubation with IFN-gamma (EXO-hOVA-IFN), bearing abundant MHC class II/OVA complexes, induced a specific humoral immune response. CONCLUSIONS: Epithelial exosomes are antigen presenting vesicles bearing MHC class II/peptide complexes that prime for an immunogenic rather than tolerogenic response in the context of a systemic challenge. In the intestine, both the mucosal microenvironment and local effector cells are probably key players in determining the outcome of the immune response to exosome derived epitopes.

Animals↗
PubMed2005

[Mechanisms and medical implications of replicative senescence].

Normal somatic cells divide in vitro only for a limited number of times, and then enter a state of replicative senescence. In most human cells replicative senescence is triggered by critical shortening and uncapping of telomeres, which leads to the up-regulation of p53 and/or p16 suppressor proteins that inhibit cell divisions. Because both reconstruction of telomeres and inactivation of suppressor proteins enables the cells to grow further or even immortalize, it has been hypothesized that replicative senescence acts as a natural barrier against neoplastic transformation. On the other hand, however, recent reports suggest that the accumulation of senescent cells may jeopardize tissue integrity and create a specific microenvironment that promotes tumorogenesis in elderly people. In this review we describe recent advances in our knowledge on the mechanisms of replicative senescence and discuss its medical implications.

Aging↗
PubMed1989

A single low dose of human recombinant interleukin 1 accelerates the recovery of neutrophils in mice with cyclophosphamide-induced neutropenia.

The actions of the cytokine interleukin 1 (IL-1) in hematopoiesis involve induction of colony-stimulating factor (CSF) production on accessory cells in the hematopoietic microenvironment and synergy with CSF on early hematopoietic progenitor cells. We have used these properties to accelerate hematologic reconstitution in granulocytopenic mice. Mice with cyclophosphamide-induced granulocytopenia were injected i.p. at day 0 with a single dose (8-800 ng) of human recombinant IL-1 alpha. At daily intervals thereafter during a period of 7 days mice were sacrificed and blood granulocytes and bone marrow cellularity were assessed. Mice receiving a single dose of 80 or 800 ng IL-1 had significantly (p less than 0.05) higher blood granulocyte counts at days 4 and 5 than control animals receiving heat-activated IL-1. This activity of IL-1 was not affected by injection of the cyclooxygenase inhibitor ibuprofen. Bone marrow cellularity, as assessed in histological sections of femurs, was significantly greater (p less than 0.05) at day 2 in mice treated with 80 or 800 ng IL-1. These results show that a single low dose of IL-1 may be used to accelerate the reconstitution of granulocytes following granulocytopenia induced with chemotherapy.

Agranulocytosis↗
PubMed2000

An acidic microenvironment impairs the generation of non-major histocompatibility complex-restricted killer cells.

The microenvironment within solid tumours has often been shown to exhibit an acidic local pH. In recent studies we could demonstrate that an acidic extracellular pH (pHe) inhibits the non-major histocompatibility complex (MHC) -restricted cytotoxicity of immunocompetent effector cells. However, within tumours the activation of cytotoxic cells may already be impaired by low pHe. Therefore, we investigated the influence of acidic conditions on the generation of active killer cells. The cytotoxic activity of natural killer (NK) as well as lymphokine-activated killer (LAK) cells against K562, Daudi and Raji cells was analysed after an activation period of 3 days at pHe 7.2-6.5. A minor reduction of pHe from 7.2 to 7.0 during the culture period resulted in a strong inhibition of the natural cytotoxicity of NK cells. Furthermore, acidic pHe below 7.2 prevented the generation of activated LAK cells by interleukin-2 (IL-2). The cytotoxic capacity could not be reconstituted if cells cultured at a pHe of 6.5 were returned to physiological pH for another 24 hr. Analysis of the cellular subtypes within the various cultures did not reveal differences regarding the frequencies of NK cells, CD8+ T cells, or CD4+ T cells. However, an acidic pHe clearly inhibited the activation-induced increase of relevant adhesion molecules. The production of cytokines which are involved in the regulation of the cytotoxic process (tumour necrosis factor-alpha, interferon-gamma, IL-10, IL-12 and transforming growth factor-beta1) was also affected by pHe, as their release was strongly inhibited at pHe 7.0. Furthermore, we observed a considerable decrease in the metabolic activity of effector cells at acidic pHe. In summary, our findings suggest that an acidic microenvironment impairs the induction of an anti-tumoral immune response within solid tumours.

CD4-Positive T-Lymphocytes↗
PubMed1986

Cell-mediated immunity in autoimmune thyroid disease.

The initiation of an autoimmune response requires the establishment of an appropriate microenvironment. This, in turn, involves several requirements, including antigen expression on the membrane surface of the target cells, class II antigen expression on the antigen-presenting cell or target cell, a relative systemic or local increase in the helper/inducer subset of T cells, and/or a relative decrease in the suppressor subset of T cells. All of these conditions have been described in the thyroid gland. Appropriate cellular interactions result in the appearance of activated T cells and the generation of cytotoxic T cells. The pathologic alterations may be produced by the local production of antibody and subsequent formation of immune complexes, by direct lymphocyte damage, or by lymphokine production. Autoimmune thyroid disease remains, to our minds, the most instructive paradigm of the organ-specific autoimmune endocrinopathies.

Animals↗
PubMed2002

Cell-surface proteolysis, growth factor activation and intercellular communication in the progression of melanoma.

Normal skin architecture and melanocyte function is maintained by a dynamic interplay between the melanocytes themselves, the epithelial cells between which they are interspersed, and their microenvironment. The microenvironment consists of the extracellular matrix, fibroblasts, migratory immune cells, and neural elements supported by a vascular network, all within a milieu of cytokines, growth factors, and bioactive peptides as well as proteolytic enzymes. Cells interact with the microenvironment via complex autocrine and paracrine mechanisms. Proteolytic enzymes in melanoma may activate or release growth factors from the microenvironment or act directly on the microenvironment itself, thereby facilitating angiogenesis or tumor cell migration. This review summarizes recent findings regarding the expression, structure and function of proteolytic enzymes at or near the cell surface in cell-cell and cell-stroma interactions during melanoma progression. Cell-surface (membrane) peptidases are a multi-functional group of ectoenzymes that have been implicated in the control of growth and differentiation of many cellular systems. The potential, but yet speculative, role of other membrane-bound molecules, such as multifunctional surface proteins with adhesion and protease activity (ADAM gene family) or the ephrin/Eph receptor protein kinases in the pathogenesis of melanoma are discussed.

Animals↗
PubMed2001

Calcium, protease activation, and cytoskeleton remodeling underlie growth cone formation and neuronal regeneration.

The cytoarchitecture, synaptic connectivity, and physiological properties of neurons are determined during their development by the interactions between the intrinsic properties of the neurons and signals provided by the microenvironment through which they grow. Many of these interactions are mediated and translated to specific growth patterns and connectivity by specialized compartments at the tips of the extending neurites: the growth cones (GCs). The mechanisms underlying GC formation at a specific time and location during development, regeneration, and some forms of learning processes, are therefore the subject of intense investigation. Using cultured Aplysia neurons we studied the cellular mechanisms that lead to the transformation of a differentiated axonal segment into a motile GC. We found that localized and transient elevation of the free intracellular calcium concentration ([Ca2+]i) to 200-300 microM induces GC formation in the form of a large lamellipodium that branches up into growing neurites. By using simultaneous on-line imaging of [Ca2+]i and of intraaxonal proteolytic activity, we found that the elevated [Ca2+]i activate proteases in the region in which a GC is formed. Inhibition of the calcium-activated proteases prior to the local elevation of the [Ca2+]i blocks the formation of GCs. Using retrospective immunofluorescent methods we imaged the proteolysis of the submembrane spectrin network, and the restructuring of the cytoskeleton at the site of GC formation. The restructuring of the actin and microtubule network leads to local accumulation of transported vesicles, which then fuse with the plasma membrane in support of the GC expansion.

Animals↗
PubMed2005

Differential proton sensitivity of related G protein-coupled receptors T cell death-associated gene 8 and G2A expressed in immune cells.

G2A, T cell death-associated gene 8 (TDAG8), ovarian cancer G protein-coupled receptor 1 (OGR1), and G protein-coupled receptor 4 (GPR4) form a group of structurally related G protein-coupled receptors (GPCRs) originally proposed to bind proinflammatory lipids. More recent studies have challenged the identification of lipid agonists for these GPCRs and have suggested that they function primarily as proton sensors. We compared the ability of these four receptors to modulate pH-dependent responses by using transiently transfected cell lines. In accordance with previously published reports, OGR1 was found to evoke strong pH-dependent responses as measured by inositol phosphate accumulation. We also confirmed the pH-dependent cAMP production by GPR4 and TDAG8. However, we found the activity of the human G2A receptor and its mouse homolog to be significantly less sensitive to pH fluctuations as measured by inositol phosphate and cAMP accumulation. Sequence homology analysis indicated that, with one exception, the histidine residues that were previously shown to be important for pH sensing by OGR1, GPR4, and TDAG8 were not conserved in the G2A receptor. We further addressed the pH-sensing properties of G2A and TDAG8 in a cellular context where these receptors are coexpressed. In thymocytes and splenocytes explanted from receptor-deficient mice, TDAG8 was found to be critical for pH-dependent cAMP production. In contrast, G2A was found to be dispensable for this process. We conclude that members of this GPCR group exhibit differential sensitivity to extracellular protons, and that expression of TDAG8 by immune cells may regulate responses in acidic microenvironments.

1-Methyl-3-isobutylxanthine↗
PubMed1998

Real-time quantitative measurement of autocrine ligand binding indicates that autocrine loops are spatially localized.

Autocrine ligands are important regulators of many normal tissues and have been implicated in a number of disease states, including cancer. However, because by definition autocrine ligands are synthesized, secreted, and bound to cell receptors within an intrinsically self-contained "loop," standard pharmacological approaches cannot be used to investigate relationships between ligand/receptor binding and consequent cellular responses. We demonstrate here a new approach for measurement of autocrine ligand binding to cells, using a microphysiometer assay originally developed for investigating cell responses to exogenous ligands. This technique permits quantitative measurements of autocrine responses on the time scale of receptor binding and internalization, thus allowing investigation of the role of receptor trafficking and dynamics in cellular responses. We used this technique to investigate autocrine signaling through the epidermal growth factor receptor by transforming growth factor alpha (TGFalpha) and found that anti-receptor antibodies are far more effective than anti-ligand antibodies in inhibiting autocrine signaling. This result indicates that autocrine-based signals can operate in a spatially restricted, local manner and thus provide cells with information on their local microenvironment.

Animals↗
PubMed1990

Adhesion of human B cells to germinal centers in vitro involves VLA-4 and INCAM-110.

Human B lymphocytes localize and differentiate within the microenvironment of lymphoid germinal centers. A frozen section binding assay was developed for the identification of those molecules involved in the adhesive interactions between B cells and lymphoid follicles. Activated human B cells and B cell lines were found to selectively adhere to germinal centers. The VLA-4 molecule on the lymphocyte and the adhesion molecule INCAM-110, expressed on follicular dendritic cells, supported this interaction. This cellular interaction model can be used for the study of how B cells differentiate.

Antibodies, Monoclonal↗