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PubMed2001

Lymphostromal interactions in thymic development and function.

The generation of a peripheral T-cell pool is essential for normal immune system function. CD4+ and CD8+ T cells are produced most efficiently in the thymus, which provides a complexity of discrete cellular microenvironments. Specialized stromal cells, that make up such microenvironments, influence each stage in the maturation programme of immature T-cell precursors. Progress has recently been made in elucidating events that regulate the development of intrathymic microenvironments, as well as mechanisms of thymocyte differentiation. It is becoming increasingly clear that the generation and maintenance of thymic environments that are capable of supporting efficient T-cell development, requires complex interplay between lymphoid and stromal compartments of the thymus.

Animals↗

PubMed1998

The influence of hypoxia and pH on aminolaevulinic acid-induced photodynamic therapy in bladder cancer cells in vitro.

Photodynamic therapy (PDT) is a cancer treatment based on the interaction of light and a photosensitizing chemical. The photosensitizer protoporphyrin IX (PpIX) is generated via the haem biosynthetic pathway after administration of aminolaevulinic acid (ALA). The cellular microenvironment of tumours is hypoxic and acidotic relative to normal tissue, which may influence PpIX generation and compromise PDT efficacy. This study used bladder cancer cells, incubated with ALA at various oxygen tensions and H+ ion concentrations, and assessed the effects on PpIX generation and PDT sensitivity. PpIX production was reduced at 0%, 2.5% (19 mmHg) and 5% (38 mmHg) oxygen compared with that at 21% (160 mmHg) oxygen (0.15, 0.28 and 0.398 ng microg(-1) protein compared with 0.68 ng microg(-1) respectively; P < 0.05). The response to PDT was abolished by hypoxia, as a result of both reduced PpIX synthesis and reduced PDT toxicity. PpIX production was greater at pH 7.0 and 6.5 (0.75 and 0.66 ng microg(-1)) compared with that at pH 7.4 and 5.5 (0.41 and 0.55 ng microg(-1) respectively). PDT cytotoxicity was enhanced at lower pH values. These results suggest that ALA-induced PDT may be inhibited by hypoxia due to reduced intrinsic PpIX synthesis. Acidosis may slightly enhance the efficacy of ALA-induced PDT.

Acidosis↗

PubMed1993

Live computerized videomicroscopy of cerebral microvessels in brain slices.

A model system for studying cerebral microvasculature is presented in which submerged in vitro brain slices are examined by computerized videomicroscopy. Brain slices are superfused continuously with artificial cerebrospinal fluid, while blood vessels are monitored using a transmission light microscope with water immersion objectives. The responses to well-characterized vasoactive compounds indicate that basic physiological characteristics are maintained in this preparation. This model system represents a simple and rapid technique for studying cerebrovascular responses under conditions in which vessels are surrounded by their normal cellular microenvironment. An additional advantage of this technique is the ability to perform simultaneous electrophysiological recordings in identified neurons. This will facilitate the study of interactions between neuronal and vascular elements and may help elucidate mechanisms underlying the local regulation of cerebral microvasculature.

Animals↗

PubMed1986

Primary active sodium transport, oxygen consumption, and ATP: coupling and regulation.

Several metabolic aspects of primary active transport have been explored in this communication. One emphasized theme entailed the need to investigate the properties of the mitochondria and the active transport systems within the intact cell. Several methodological and conceptual approaches were described that permitted such an analysis. The answers provided were sometimes qualitative or quantitative. Qualitative information was provided regarding the cytosolic signal linking active transport with respiration, suggesting that the cytosolic ADP concentration was an important element in that link. The intact renal cell was found to work normally at 50 to 60% of its maximal respiratory capacity, indicating that sufficient reserve capacity was present for increased metabolic demands. Several examples were described in which a combination of qO2 measurements and/or optical techniques were used to differentiate between effects of agents which act primarily on transport or metabolic events. Finally, the control of transport by metabolism was discussed, primarily emphasizing the role of ATP and Pi. One of the overall conclusions from these studies is that, in general, the mitochondria and the transport systems seem to display similar properties in the intact cell as they do in isolated form. However, uncertainties concerning the cellular microenvironment surrounding the mitochondria and the plasma membrane transporters have produced some interesting surprises concerning their function in the intact cell. More quantitative information on the energy compartmentation of the renal cell would be helpful to clarify numerous aspects of metabolic function.

Adenosine Diphosphate↗

PubMed2001

The immunological synapse and CD28-CD80 interactions.

According to the two-signal model of T cell activation, costimulatory molecules augment T cell receptor (TCR) signaling, whereas adhesion molecules enhance TCR-MHC-peptide recognition. The structure and binding properties of CD28 imply that it may perform both functions, blurring the distinction between adhesion and costimulatory molecules. Our results show that CD28 on naïve T cells does not support adhesion and has little or no capacity for directly enhancing TCR-MHC-peptide interactions. Instead of being dependent on costimulatory signaling, we propose that a key function of the immunological synapse is to generate a cellular microenvironment that favors the interactions of potent secondary signaling molecules, such as CD28.

B7-1 Antigen↗

PubMed2006

Capturing complex 3D tissue physiology in vitro.

The emergence of tissue engineering raises new possibilities for the study of complex physiological and pathophysiological processes in vitro. Many tools are now available to create 3D tissue models in vitro, but the blueprints for what to make have been slower to arrive. We discuss here some of the 'design principles' for recreating the interwoven set of biochemical and mechanical cues in the cellular microenvironment, and the methods for implementing them. We emphasize applications that involve epithelial tissues for which 3D models could explain mechanisms of disease or aid in drug development.

Animals↗

PubMed1998

p53 mediates apoptosis induced by c-Myc activation in hypoxic or gamma irradiated fibroblasts.

Deregulated c-Myc expression leads to a cellular state where proliferation and apoptosis are equally favored depending on the cellular microenvironment. Since the apoptotic sensitivity of many cells is influenced by the status of the p53 tumor suppressor gene, we investigated whether the induction of apoptosis by DNA damage or non-genotoxic stress are also influenced by the p53 status of cells with altered c-Myc activity. Rat-1 fibroblasts expressing a conditional c-Myc allele (c-MycER), were transfected to express an antisense RNA complimentary to p53 mRNA. Expression of antisense p53 RNA decreased p53 protein levels and delayed p53 accumulation following c-Myc activation. Under hypoxic or low serum conditions, cells expressing antisense p53 were substantially more resistant to c-Myc-induced apoptosis than were control cells. c-Myc activation also sensitized Rat-1 cells to radiation-induced apoptosis. Rat-1 cells expressing antisense p53 RNA were more resistant to apoptosis induced by the combined effects of c-Myc activation and gamma irradiation. In a similar manner, apoptosis induced by c-Myc in serum starved, hypoxic or gamma irradiated fibroblasts was also inhibited by Bcl-2. These data indicate that p53 is involved in c-Myc-mediated apoptosis under a variety of stresses which may influence tumor growth, evolution and response to therapy.

Animals↗

PubMed2005

Adenoviral proteins mimic nutrient/growth signals to activate the mTOR pathway for viral replication.

Like tumor cells, DNA viruses have had to evolve mechanisms that uncouple cellular replication from the many intra- and extracellular factors that normally control it. Here we show that adenovirus encodes two proteins that activate the mammalian target of rapamycin (mTOR) for viral replication, even under nutrient/growth factor-limiting conditions. E4-ORF1 mimics growth factor signaling by activating PI3-kinase, resulting in increased Rheb.GTP loading and mTOR activation. E4-ORF4 is redundant with glucose in stimulating mTOR, does not affect Rheb.GTP levels and is the major mechanism whereby adenovirus activates mTOR in quiescent primary cells. We demonstrate that mTOR is activated through a mechanism that is dependent on the E4-ORF4 protein phosphatase 2A-binding domain. We also show that mTOR activation is required for efficient S-phase entry, independently of E2F activation, in adenovirus-infected quiescent primary cells. These data reveal that adenovirus has evolved proteins that activate the mTOR pathway, irrespective of the cellular microenvironment, and which play a requisite role in viral replication.

Adenoviridae↗

PubMed2006

Fibrin microbeads (FMB) as a 3D platform for kidney gene and cell therapy.

Cell and gene therapy may alter the outcome of renal diseases, such as hereditary nephropathies, acute and chronic glomerulonephritis and allograft nephropathy. However, owing to blockade of many viral and cellular vehicles by the complex glomerular architecture, the exact nature of gene and cell delivery into specific renal compartments remains currently unknown. To study the interaction of viral vectors with a variety of renal cells and mesenchymal stem cells (MSCs), we employed a novel biological three-dimensional (3D) matrix comprised of fibrin microbeads (FMB) in comparison to monolayer cell culture. Our studies showed that renal cells of both established and primary lines can grow efficiently on FMB and differentiate into epithelial structures, as shown by electron microscopy. Gene delivery into renal cells in 3D was observed for several viral vectors and growth in 3D on FMB conferred resistance to renal cancer cells in the context of oncolytic adenoviruses. Finally, MSCs from various rodent species attached to FMB, grew robustly, survived for several weeks and could efficiently be transduced on FMB. Thus, on the basis of growth, differentiation and transduction of renal cells in 3D, FMB emerge as a novel 3D cellular microenvironment that differs substantially from monolayer cell cultures.

Cell Differentiation↗

PubMed2000

The matrix metalloproteinase stromelysin-1 acts as a natural mammary tumor promoter.

Extracellular matrix-degrading matrix metalloproteinases (MMPs) are invariably upregulated in epithelial cancers and are key agonists in angiogenesis, invasion and metastasis. Yet most MMPs are secreted not by the cancer cells themselves, but by stromal cells within and around the tumor mass. Because the stromal environment can influence tumor formation, and because MMPs can alter this environment, MMPs may also contribute to the initial stages of cancer development. Several recent studies in MMP-overexpressing and MMP-deficient mice support this possibility, but have required carcinogens or pre-existing oncogenic mutations to initiate tumorigenesis. Here we review the spontaneous development of premalignant and malignant lesions in the mammary glands of transgenic mice that express an autoactivating form of MMP-3/stromelysin-1 under the control of the whey acidic protein gene promoter. These changes were absent in nontransgenic littermates and were quenched by co-expression of a human tissue inhibitor of metalloproteinases-1 (TIMP-1) transgene. Thus by altering the cellular microenvironment, stromelysin-1 can act as a natural tumor promoter and enhance cancer susceptibility.

Animals↗

PubMed2002

Selective clonal expansion and microenvironmental permissiveness in tobacco carcinogenesis.

Historically our knowledge about the direct carcinogenic activity of cigarette smoke and its constituents grew from painting experiments on the skin of mice to produce papillomas and carcinomas. The neutral fraction of cigarette smoke condensate had most of the carcinogenic activity in this test and was rich in carcinogenic polycyclic aromatic hydrocarbons (PAHs), the most abundant by far being BP. However, the concentration of BP in the condensate was only about 2% the amount of pure BP required to cause skin tumors. In other fractions there were non-carcinogenic constituents that promoted tumor formation when applied repeatedly to mouse skin that had been initiated by a single subcarcinogenic application of BP. There were also constituents of cigarette smoke that acted as co-carcinogens when applied simultaneously with repeated applications of BP. BP was effective as an initiator at lower concentrations than as a complete carcinogen, and some non-carcinogenic PAHs in the condensate were also active initiators. It was concluded from these studies that cigarette smoke condensate is primarily a tumor-promoting and co-carcinogenic agent with weak activity as a complete carcinogen. A major effect of promoters, and possibly of co-carcinogens, is a diffuse hyperplasia which includes selective expansion of clones carrying endogenous mutations and/or mutations induced by PAHs and other carcinogens such as NNK. The induced mutations as well as damaged cells would occur throughout the exposed region and, along with the hyperplasia, increase the permissiveness of the cellular microenvironment for neoplastic expression of any potential tumor cell in its midst. Since neither the promoters nor co-carcinogens in tobacco smoke are known to interact directly with DNA, their effects can be considered epigenetic processes that act upon genetically altered cells. Examples are cited from studies of experimental skin carcinogenesis, smoking-induced histopathological changes in human lung and spontaneous transformation in cell culture to illustrate the genetic and epigenetic interactions of neoplastic development in general and their significance for smoking-induced lung cancer in particular. Certain dietary modifications that appear to be effective in moderating the promotional phase of animal and human carcinogenesis are suggested for trial in managing lung cancer.

Animals↗

PubMed1997

Structure-activity relationship of heparan sulphate.

HS influences fundamental cellular properties and biochemical processes at the cell surface. In addition to the issues already discussed, it has a profound effect on cell adhesion and migration through its interaction with many extracellular matrix proteins, most notably fibronectin and thrombospondin; it is closely linked to lipid metabolism through its capacity to bind low-density lipoprotein and lipoprotein lipase; and aberrations in HS structure and degradation are linked to human malignancy and Alzheimer's disease [26,27]. The subtle variations in HS structure enable it to distinguish between families of related proteins such as the FGFs, the chemokines [28] and the TGF beta s [29]. The multifunctional nature of HS is the result of its structural diversity and strategic positioning in the pericellular domain. The biosynthesis of HS, in common with other complex carbohydrates, is not directed by any known template yet the system is clearly subject to quite precise control so that in general, the HS family has a common domain organization that is finely tuned at the cellular level to produce HS species of variable length, fine structure and biological properties. A major challenge for future research will be to unravel the regulatory mechanisms that determine the molecular structure of HS. It remains unclear whether these mechanisms are entirely intrinsic in nature or subject to substantial modulation by the cellular microenvironment.

Alzheimer Disease↗

PubMed1999

Cell interactions control the fate of malignant keratinocytes in an organotypic model of early neoplasia.

The role of cell interactions during early neoplastic progression in human skin is not well understood. We report that the fate and behavior of low-grade malignant cells in stratified epithelium is dependent on their interactions with neighboring cells and with extracellular matrix during the early events in neoplastic progression. We utilized an organotypic tissue model which mimics premalignancy to monitor malignant cells (II-4) genetically marked with beta-gal and grown in the context of either normal human keratinocytes or the immortalized cell line HaCaT. HaCaT cells were permissive for clonal expansion of II-4 cells at ratios of 4:1, 12:1, and 50:1 (HAC:II-4) when compared with coculture with normal human keratinocytes. This II-4 cell expansion was associated with the failure of neighboring HaCaT cells to induce differentiation and cell cycle withdrawal of II-4, as had been seen in the context of normal human keratinocytes. When 12:1 mixtures (NHK:II-4) were stripped of all suprabasal cells and regrown, all beta-gal cells were lost showing that these normal human keratinocyte-suppressed II-4 cells had been actively sorted to a suprabasal position where their clonal expansion was limited. These growth-suppressive effects of normal human keratinocytes were found to be conditional on direct cell-cell contact, as II-4 formed colonies when trypsinized from 12:1 (NHK:II-4) mixtures and grown at clonal density in submerged culture. The distribution and behavior of low-grade malignant cells was therefore dependent on the state of transformation of adjacent keratinocytes and on cell-matrix interactions. These results demonstrate that alterations in the cellular microenvironment are central to the induction of clonal expansion and early neoplastic progression in stratified epithelium.

Cell Communication↗

PubMed2002

Inducible nitric oxide synthase in renal transplantation.

The importance of the endothelial isoform of nitric oxide synthase (eNOS) has been well established. Endothelium-derived nitric oxide has been shown to be essential for vascular homeostasis and modulation of eNOS has thus become a target in prevention of cardiovascular disease. The role of the inducible form of nitric oxide synthase (iNOS) in vascular biology, however, is less clear. Classically, iNOS has been regarded as an enzyme that produces nmolar amounts of the nitric oxide radical, thereby leading to cellular damage. More recent data, however, have shown that the iNOS can be a superoxide, peroxynitrite as well as a nitric oxide-producing enzyme, while the biological effects of iNOS probably depend upon the sort of radical species released by the enzyme as well as the anti-oxidant capacity of the cellular microenvironment of the enzyme. This brief review discusses these aspects in relation to renal transplantation.

Acute Disease↗

PubMed2000

A possible role of soluble receptors to cell growth factors in body aging.

It is assumed that production by differentiated cells of soluble receptors to cell growth factors may mediate a feedback mechanism controlling cell growth and differentiation in the body. Based on this assumption, it is hypothesized that with age a concentration of such soluble receptors in the body fluids gradually augments as a consequence of increasing a proportion of the differentiated cell pool. In the old body, when present in the cellular microenvironment at relatively high concentrations these receptors might markedly diminish ligand binding to the membrane-bound counterparts in a competitive manner and, thereby, significantly reduce cell regeneration activity. Under such conditions, the niches forming because of cell death could be being filled by connective fibers rather than newly generated cells.

Aging↗

PubMed2000

Molecular biology of ryudocan, an endothelial heparan sulfate proteoglycan.

Ryudocan is a type I integral membrane heparan sulfate proteoglycan, which was originally cloned from rat microvascular endothelial cells. We have cloned the cDNA of rat ryudocan. The deduced amino acids of ryudocan has homologous transmembrane and intracellular domains with syndecan but very distinct extracellular regions. We also cloned the human ryudocan cDNA, of which the gene localizes on the chromosome 20q12. To better understand the regulation of ryudocan expression, we have determined the structural organization of the human ryudocan gene. The human ryudocan gene extends approximately 24 kb and is divided into five exons that appear conserved in syndecan family members. The 5'-flanking sequences of the human ryudocan gene contain a variety of potential binding sites for transcription factors and are capable of functioning as a promoter. We purified human ryudocan and evaluated its interactions with several extracellular ligands. It was found that basic fibroblast growth factor (bFGF), midkine, and tissue factor pathway inhibitor exhibited significant ryudocan bindings. Heparitinase, but not chondroitin ABC lyase treatment, destroyed those ryudocan bindings; thus, the heparan sulfate chains of ryudocan appear to be responsible for those bindings. Immunohistochemical analysis revealed that ryudocan is expressed in peripheral nerve tissues, fibrous connective tissues, and placental trophoblasts. These findings suggest that ryudocan may possess multiple biologic functions, such as bFGF modulation, neurite growth promotion, and anticoagulation, via heparan sulfate-binding effectors in the cellular microenvironment.

Amino Acid Sequence↗

PubMed2006

Local myocardial insulin-like growth factor 1 (IGF-1) delivery with biotinylated peptide nanofibers improves cell therapy for myocardial infarction.

Strategies for cardiac repair include injection of cells, but these approaches have been hampered by poor cell engraftment, survival, and differentiation. To address these shortcomings for the purpose of improving cardiac function after injury, we designed self-assembling peptide nanofibers for prolonged delivery of insulin-like growth factor 1 (IGF-1), a cardiomyocyte growth and differentiation factor, to the myocardium, using a "biotin sandwich" approach. Biotinylated IGF-1 was complexed with tetravalent streptavidin and then bound to biotinylated self-assembling peptides. This biotin sandwich strategy allowed binding of IGF-1 but did not prevent self-assembly of the peptides into nanofibers within the myocardium. IGF-1 that was bound to peptide nanofibers activated Akt, decreased activation of caspase-3, and increased expression of cardiac troponin I in cardiomyocytes. After injection into rat myocardium, biotinylated nanofibers provided sustained IGF-1 delivery for 28 days, and targeted delivery of IGF-1 in vivo increased activation of Akt in the myocardium. When combined with transplanted cardiomyocytes, IGF-1 delivery by biotinylated nanofibers decreased caspase-3 cleavage by 28% and increased the myocyte cross-sectional area by 25% compared with cells embedded within nanofibers alone or with untethered IGF-1. Finally, cell therapy with IGF-1 delivery by biotinylated nanofibers improved systolic function after experimental myocardial infarction, demonstrating how engineering the local cellular microenvironment can improve cell therapy.

Animals↗

PubMed1981

Growth regulation, reverse transformation, and adaptability of 3T3 cells in decreased Mg2+ concentration.

A nontransformed and a spontaneously transformed clone of BALB/c 3T3 cells were compared for their capacity to multiply in decreased concentrations of Mg(2+). Cells of the nontransformed clone were flat, formed regularly patterned, nonoverlapping arrays, required high serum concentration for multiplication, had a low saturation density, and did not make colonies in agar. Cells of the transformed clone were slender and spiky, formed random, overlapping arrays, multiplied in low serum concentrations, and had no fixed saturation density, and 20-30% of them formed colonies in agar. The saturation density of the nontransformed clone was decreased in a growth-limiting supply of Mg(2+) in proportion to the reduction in initial rate of multiplication. At very low Mg(2+) concentrations, saturation occurred when less than half of the surface of the dish was covered with cells. The transformed cells did not reach a stable saturation density in low Mg(2+) concentrations, but their growth rate did slow down when they became crowded, and a transient saturation density was reached at the lowest Mg(2+) concentrations that allowed multiplication. Limiting the supply of Mg(2+) caused the transformed cells to flatten and to assume a regularly patterned, non-overlapping relationship to one another, resembling that of the nontransformed cells. This also occurred in BALB/c 3T3 cells transformed by infection with Moloney mouse sarcoma virus. After 1 week in low concentrations of Mg(2+), the nontransformed cells began to multiply and to incorporate [(3)H]thymidine at a rapid rate. The transformed cells did so also and, in addition, reverted to their transformed appearance. The intracellular content of Mg(2+) was not significantly decreased when the extracellular concentration was decreased to 1/50th. The results suggest that: (a) limited contact among cells already multiplying at a reduced rate is sufficient to halt further multiplication; (b) a very small decrease in intracellular Mg(2+) content or in membrane-associated Mg(2+) causes transformed cells to assume aspects of the appearance and behavior of nontransformed cells (i.e., Mg(2+)-regulated reactions may be involved in determining the transformed phenotype); and (c) cells multiplying at a slow rate in low concentrations of Mg(2+) begin to multiply faster after about 1 week, due either to an adaptation of the cells or to a change in the cellular microenvironment.

Animals↗