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PubMed2004

Extracellular regulation of TGF-beta activity in wound repair: growth factor latency as a sensor mechanism for injury.

The transforming growth factor-beta (TGFbeta) family of growth factors are major regulators of wound repair, scar formation, and fibrosis. One of the prominent features of TGFbeta biology is the fact that this growth factor is secreted as a latent precursor, which may be directed to and stored at specific sites in the cellular microenvironment. Targeting and mobilization, and particularly extracellular activation of latent TGF-beta control the biological action of this growth factor. This review will focus on mechanisms of extracellular TGF-beta regulation relevant to and potentially operating in wound repair and scarring.

Animals↗
PubMed1998

Probing heterotypic cell interactions: hepatocyte function in microfabricated co-cultures.

Replacement of liver function using extracorporeal bioartificial systems has been attempted with limited success. The instability of the hepatocyte phenotype in vitro has restricted the useful lifetime of these devices. Co-cultivation of hepatocytes with mesenchymal cells is one method that has been widely utilized to stabilize the liver-specific function of isolated cells; however, co-culture has yet to be successfully incorporated in a bioreactor setting. In this study, we probed heterotypic cell interactions in co-cultures of hepatocytes and 3T3 in order to better understand the cellular microenvironment necessary to induce and stabilize liver-specific functions. Using microfabrication and conventional techniques to control the heterotypic interface, the effects of varying degrees of heterotypic interaction on tissue function (albumin and urea synthesis) were examined. Our data indicated maximal induction of liver-specific functions in cultures with maximal initial heterotypic interaction, and that induction of hepatic functions in hepatocytes was increased in the vicinity of fibroblasts as compared to hepatocytes far from the heterotypic interface. Furthermore, our data suggested that heterotypic cell contact is necessary for induction of these functions. These studies will aid in the formation of design criteria for a co-culture based bioartificial liver, as well as provide a useful tool to study the role of heterotypic and homotypic interactions in liver physiology and pathophysiology.

3T3 Cells↗
PubMed1990

Alveolar type II cell responses to chronic inhalation of chrysotile asbestos in rats.

The effects of chronic exposure to chrysotile asbestos on alveolar type II cells were examined in the lungs of Fischer 344 rats. Morphometric and three-dimensional analyses were used to characterize the alveolar type II cell and to determine the relationship of asbestos fiber localization to ultrastructural change in these cells. During the 2-yr period of study, type II cell number and volume increased to values more than 4 times those seen in controls. Ultrastructurally, cisternal dilations of the rough endoplasmic reticulum (RER) composed 12% of the total cell volume after 12 mo of exposure to asbestos and was still 15% of the total cell volume 1 yr after fiber exposure had ended compared to less than 1% in control cells. Asbestos fiber density surrounding these cells was directly proportional to the degree of cisternal dilatation in the cell; however, lamellar body volume and number in these cells were not different from that found in control type II cells. The incidence of a subset of type II cells with large lamellated inclusions was 10-fold greater in regions near bronchiolar-alveolar duct junctions, compared to more distal gas exchange regions of the lungs. Normal-sized lamellar bodies were fused to these large lamellated inclusions. These cells also contained significantly greater numbers of lamellar bodies and multivesicular bodies than those type II cells in more distal lung regions. These ultrastructural changes observed in type II cells may be a simple dose response to inhaled asbestos or the manifestation of two distinct populations of cells in the lungs that respond to asbestos in different ways. Asbestos fiber dose, cellular microenvironment, and aberrations of the cell plasma membrane and/or cell cytoskeleton (i.e., microtubules and filaments) are discussed as potential factors in the changes noted in type II cells.

Administration, Inhalation↗
PubMed2006

Galactose derivative immobilized glow discharge processed polyethersulfone membranes maintain the liver cell metabolic activity.

New strategies aimed to surface modification of polymeric membranes are crucial to optimise cell-biomaterial interactions in vivo and in vitro biohybrid systems. In this paper, we investigated the surface modification of Polyethersulfone (PES) membranes by plasma polymerisation of acrylic acid monomers (PES-pdAA) and by immobilization of galactonic acid through a hydrophilic "spacer arm" molecule (PES-pdAA-SA-GAL). The modification steps were characterised by high resolution X-ray photoelectron spectroscopy. The performance of modified and unmodified membranes was evaluated by assessing the expression of liver specific biotransformation functions of pig and human hepatocytes. Human liver cells cultured on PES-pdAA-SA-GAL membranes displayed an enhanced albumin production, urea synthesis and protein secretion for 24 days of culture. The immobilisation of galactose derivative units on the membrane allowed specific interactions with hepatocytes biomimicking the cellular microenvironment and produced an improvement of the long-term maintenance and differentiation of human hepatocytes.

Acrylates↗
PubMed1976

Plasma protein immunocytochemistry and polysaccharide cytochemistry at the surface of alveolar and endothelial cells in the rat lung.

Ultrastructural immunocytochemistry of plasma proteins and cytochemistry of polysaccharides with ruthenium red and concanavalin A were combined with different types of fixation with or without prior vascular or airway washing, to study the surface of capillary endothelial and alveolar epithelial cells of the blood-air barrier in the rat lung. The endothelial and epithelial cell surface layers were found to have two components: a moveable part belonging to the cellular microenvironement made of plasma proteins and a deeper glucidic or anionic fixed part bound to the plasma membranes (cell coat).

Animals↗
PubMed2005

Unique toxicities and resistance mechanisms associated with monoclonal antibody therapy.

Anti-CD20 therapy has had a truly dramatic impact on treatment and outcome of patients with follicular lymphoma. Unfortunately, the majority of responses to single-agent rituximab are incomplete, and all patients with follicular lymphoma will experience disease progression at some point following rituximab therapy. Rituximab has multiple mechanisms of inducing in vivo cytotoxicity, including antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, direct apoptotic signaling, and possible vaccinal effects. The cellular microenvironment within follicular lymphoma has a profound impact on which mechanism is dominant, and confers resistance in many situations. Both tumor-associated and host-associated factors also contribute to rituximab resistance. There are multiple potential approaches to overcoming rituximab resistance, including rational biologic combination immunotherapy, engineered antibodies, and radioimmunoconjugates. Improved ability to overcome resistance will require further elucidation of critical signaling pathways involved in rituximab induced cytotoxicity and a comprehensive understanding of interactions between its multiple mechanisms of action.

Antibodies, Monoclonal↗
PubMed2004

Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness.

Infusion of either embryonic or mesenchymal stem cells prolongs the survival of organ transplants derived from stem cell donors and prevents graft-versus-host-disease (GVHD). An in-depth mechanistic understanding of this tolerization phenomenon could lead to novel cell-based therapies for transplantation. Here we demonstrate that while human mesenchymal stem cells (hMSCs) can promote superantigen-induced activation of purified T cells, addition of antigen-presenting cells (APCs; either monocytes or dendritic cells) to the cultures inhibits the T-cell responses. This contact- and dose-dependent inhibition is accompanied by secretion of large quantities of interleukin (IL)-10 and aberrant APC maturation, which can be partially overridden by the addition of factors that promote APC maturation (ie, lipopolysaccharide [LPS] or anti-CD40 monoclonal antibody [mAb]). Thus, our data support an immunoregulatory mechanism wherein hMSCs inhibit T cells indirectly by contact-dependent induction of regulatory APCs with T-cell-suppressive properties. Our data may reveal a physiologic phenomenon whereby the development of a distinct APC population is regulated by the tissue's cellular microenvironment.

Antigen-Presenting Cells↗
PubMed2006

Human mesenchymal stem cells isolated from bone marrow and lymphoid organs support tumor B-cell growth: role of stromal cells in follicular lymphoma pathogenesis.

Accumulating evidence indicates that the cellular microenvironment plays a key role in follicular lymphoma (FL) pathogenesis, both within tumor lymph nodes (LNs) and in infiltrated bone marrow where ectopic LN-like reticular cells are integrated within malignant B-cell nodular aggregates. In normal secondary lymphoid organs, specific stromal cell subsets provide a highly specialized microenvironment that supports immune response. In particular, fibroblastic reticular cells (FRCs) mediate immune cell migration, adhesion, and reciprocal interactions. The role of FRCs and their postulated progenitors, that is, bone marrow mesenchymal stem cells (MSCs), in FL remains unexplored. In this study, we investigated the relationships between FRCs and MSCs and their capacity to sustain malignant B-cell growth. Our findings strongly suggest that secondary lymphoid organs contain MSCs able to give rise to adipocytes, chondrocytes, osteoblasts, as well as fully functional B-cell supportive FRCs. In vitro, bone marrow-derived MSCs acquire a complete FRC phenotype in response to a combination of tumor necrosis factor-alpha and lymphotoxin-alpha1beta2. Moreover, MSCs recruit primary FL cells that, in turn, trigger their differentiation into FRCs, making them able to support malignant B-cell survival. Altogether, these new insights into the cross talk between lymphoma cells and their microenvironment could offer original therapeutic strategies.

Bone Marrow Cells↗
PubMed2005

Estradiol regulates different genes in human breast tumor xenografts compared with the identical cells in culture.

In breast cancers, estrogen receptor (ER) levels are highly correlated with response to endocrine therapies. We sought to define mechanisms of estrogen (E) signaling in a solid breast tumor model using gene expression profiling. ER(+) T47D-Y human breast cancer cells were grown as xenografts in ovariectomized nude mice under four conditions: 1) 17beta-estradiol for 8 wk (E); 2) without E for 8 wk (control); 3) E for 7 wk followed by 1 wk of E withdrawal (Ewd); or 4) E for 8 wk plus tamoxifen for the last week. E-regulated genes were defined as those that differed significantly between control and E and/or between E and Ewd or control and Ewd. These protocols generated 188 in vivo E-regulated genes that showed two major patterns of regulation. Approximately 46% returned to basal states after Ewd (class I genes); 53% did not (class II genes). In addition, more than 70% of class II-regulated genes also failed to reverse in response to tamoxifen. These genes may be interesting for the study of hormone-resistance issues. A subset of in vivo E-regulated genes appears on lists of clinical ER discriminator genes. These may be useful therapeutic targets or markers of E activity. Comparison of in vivo E-regulated genes with those regulated in identical cells in vitro after 6 and 24 h of E treatment demonstrate only 11% overlap. This indicates the extent to which gene expression profiles are uniquely dependent on hormone-treatment times and the cellular microenvironment.

Analysis of Variance↗
PubMed1994

Laminin and tenascin assembly and expression regulate HC11 mouse mammary cell differentiation.

HC11 is a normal mouse mammary epithelial cell line that requires certain growth factors, such as EGF or bFGF, to respond optimally to lactogenic hormones and produce the differentiation marker beta-casein. Growth in insulin (Ins) or PDGF does not produce cells competent to respond to lactogenic hormones. Here we show that competency for differentiation is due at least in part to the modulation of extracellular matrix components. In particular we have studied laminin and tenascin. EGF alters endogenous laminin assembly. In addition, promotion of competency can be partially mimicked by plating HC11 cells on the E8 laminin fragment, which is able to induce lactogenic responsiveness in cells grown in the absence of EGF or bFGF. The production and assembly of tenascin is also dependent upon the growth conditions of the HC11 cells. EGF- or bFGF-grown competent cells produce tenascin but do not assemble it at the extracellular matrix as efficiently as Ins- or PDGF-grown, non-competent cells. This alteration apparently leads to a change in the cellular microenvironment that supports beta-casein production. In addition, when competent cells are plated on dishes coated with tenascin, lactogenic hormone induction of beta-casein is inhibited. The data suggest that tenascin assembly and beta-casein production are opposing features of a coordinated differentiation program of HC11 cells.

Animals↗
PubMed2000

Human bone-derived cells support formation of human osteoclasts from arthroplasty-derived cells in vitro.

Mononuclear osteoclast precursors are present in the wear-particle-associated macrophage infiltrate found in the membrane surrounding loose implants. These cells are capable of differentiating into osteoclastic bone-resorbing cells when co-cultured with the rat osteoblast-like cell line, UMR 106, in the presence of 1,25(OH)2 vitamin D3. In order to develop an in vitro model of osteoclast differentiation which more closely parallels the cellular microenvironment at the bone-implant interface in situ, we determined whether osteoblast-like human bone-derived cells were capable of supporting the differentiation of osteoclasts from arthroplasty-derived cells and analysed the humoral conditions required for this to occur. Long-term co-culture of arthroplasty-derived cells and human trabecular-bone-derived cells (HBDCs) resulted in the formation of numerous tartrate-resistant-acid-phosphatase (TRAP) and vitronectin-receptor (VNR)-positive multinucleated cells capable of extensive resorption of lacunar bone. The addition of 1,25(OH)2 vitamin D3 was not required for the formation of osteoclasts and bone resorption. During the formation there was release of substantial levels of M-CSF and PGE2. Exogenous PGE2 (10(-8) to 10(-6) M) was found to stimulate strongly the resorption of osteoclastic bone. Our study has shown that HBDCs are capable of supporting the formation of osteoclasts from mononuclear phagocyte precursors present in the periprosthetic tissues surrounding a loose implant. The release of M-CSF and PGE2 by activated cells at the bone-implant interface may be important for the formation of osteoclasts at sites of pathological bone resorption associated with aseptic loosening.

Acid Phosphatase↗
PubMed2005

Niche-independent symmetrical self-renewal of a mammalian tissue stem cell.

Pluripotent mouse embryonic stem (ES) cells multiply in simple monoculture by symmetrical divisions. In vivo, however, stem cells are generally thought to depend on specialised cellular microenvironments and to undergo predominantly asymmetric divisions. Ex vivo expansion of pure populations of tissue stem cells has proven elusive. Neural progenitor cells are propagated in combination with differentiating progeny in floating clusters called neurospheres. The proportion of stem cells in neurospheres is low, however, and they cannot be directly observed or interrogated. Here we demonstrate that the complex neurosphere environment is dispensable for stem cell maintenance, and that the combination of fibroblast growth factor 2 (FGF-2) and epidermal growth factor (EGF) is sufficient for derivation and continuous expansion by symmetrical division of pure cultures of neural stem (NS) cells. NS cells were derived first from mouse ES cells. Neural lineage induction was followed by growth factor addition in basal culture media. In the presence of only EGF and FGF-2, resulting NS cells proliferate continuously, are diploid, and clonogenic. After prolonged expansion, they remain able to differentiate efficiently into neurons and astrocytes in vitro and upon transplantation into the adult brain. Colonies generated from single NS cells all produce neurons upon growth factor withdrawal. NS cells uniformly express morphological, cell biological, and molecular features of radial glia, developmental precursors of neurons and glia. Consistent with this profile, adherent NS cell lines can readily be established from foetal mouse brain. Similar NS cells can be generated from human ES cells and human foetal brain. The extrinsic factors EGF plus FGF-2 are sufficient to sustain pure symmetrical self-renewing divisions of NS cells. The resultant cultures constitute the first known example of tissue-specific stem cells that can be propagated without accompanying differentiation. These homogenous cultures will enable delineation of molecular mechanisms that define a tissue-specific stem cell and allow direct comparison with pluripotent ES cells.

Animals↗
PubMed2003

The heme oxygenase dilemma in cellular homeostasis: new insights for the feedback regulation of heme catabolism.

Heme must be synthesized and degraded within an individual nucleated cell. Heme degradation is catalyzed by the two isozymes of heme oxygenase, heme oxygenase-1 (HO-1) and HO-2, eventually yielding biliverdin/bilirubin, CO, and iron. These products possess important physiological roles but are potentially toxic to cells. Characteristically, human HO-1 contains no Cys residues, whereas HO-2 contains the potential heme-binding motifs of the Cys-Pro dipeptide. Expression of HO-1 is inducible or repressible, depending on cell types or cellular microenvironments, but expression levels of HO-2 are fairly constant. Thus, the main regulation of heme catabolism is a problem of the balance between induction and repression of HO-1. Notably, HO-1 expression is induced by heme in all mammalian cells examined, but is repressed by hypoxia in certain types of cultured human cells. The recent discovery of Bach1 as a heme-regulated and hypoxia-inducible repressor for transcription of the HO-1 gene has provided a missing link in the feedback control of heme catabolism. On the other hand, the human HO-1 gene promoter contains the (GT)n repeat polymorphism and a single nucleotide polymorphism (-427A --> T), both of which may contribute to fine-tuning of the transcription. Importantly, long (GT)n alleles are associated with susceptibility to smoking-induced emphysema or coronary artery disease, but may provide with resistance to cerebral malaria. The latter finding suggests a novel therapeutic strategy with inhibitors of HO-1 for the treatment of cerebral malaria. We discuss the potential regulatory role of Bach1 and HO-2 in heme catabolism and update the understanding of the regulation of HO-1 expression.

Animals↗
PubMed2006

Aqueous humor enhances the proliferation of rat retinal precursor cells in culture, and this effect is partially reproduced by ascorbic acid.

Aqueous humor has been shown to influence the proliferation of various ocular cell types, but the effect on immature retinal cells is not known. Here, the effect of pig aqueous humor on the proliferation of rat retinal precursor cells (RPCs) was investigated. RPCs were prepared from embryonic day 19 Sprague-Dawley rats and cultured in the presence or absence of aqueous humor from healthy pigs along with a medium consisting of Dulbecco's modified Eagle's medium:Ham's F-12 medium, N2 supplement, and epidermal growth factor. Proliferation was quantified by [(3)H]thymidine incorporation under different treatment conditions, and any associated morphological changes were noted. Potential active components of porcine aqueous humor were partially characterized by gel filtration chromatography, and the effect on RPC proliferation was determined. Results showed that adding 20% aqueous humor increased [(3)H]thymidine incorporation by as much as 317%, as compared with controls. Aqueous supplementation also increased both the number and size of RPC spherical aggregates ("spheres") over the first 4 days, consistent with increased proliferative activity. Using gel filtration and the in vitro proliferation assay, the growth-promoting activity of aqueous humor was localized to two different molecular mass ranges, namely, around 30 kDa and less than 1 kDa. Ascorbic acid was present in the lower molecular mass fraction, and use of this molecule reproduced some, but not all, of the proliferative activity present in aqueous humor. These results highlight the potential role of soluble factors present in the cellular microenvironment with respect to modulation of endogenous progenitor cell activity.

Animals↗
PubMed2004

Dendritic cell development in long-term spleen stromal cultures.

The cellular microenvironments in which dendritic cells (DCs) develop are not known. DCs are commonly expanded from CD34+ bone marrow precursors or blood monocytes using a cocktail of growth factors including GM-CSF. However, cytokine-supported cultures are not suitable for studying the intermediate stages of DC development, since progenitors are quickly driven to become mature DCs that undergo limited proliferation and survive for only a short period of time. This lab has developed a long-term culture (LTC) system from spleen which readily generates a high yield of DCs. Hematopoietic cells develop under more normal physiological conditions than in cultures supplemented with cytokines. A spleen stromal cell monolayer supports stem cell maintenance, renewal, and the specific differentiation of only DCs and no other hematopoietic cells. Cultures maintain continuous production of a small population of small-sized progenitors and a large population of fully developed DCs. Cell-cell interaction between stromal cells and progenitor cells is critical for DC differentiation. The progenitors maintained in LTC appear to be quite distinct from bone marrow-derived DC progenitors that respond to GM-CSF. The majority of cells produced in LTC are large-sized cells with a phenotype reflecting myeloid-like DC precursors or immature DCs. These cells are highly endocytotic and weakly immunostimulatory for T cells. This model system predicts in situ production of DCs in spleen from endogenous progenitors, as well as a central role for spleen in DC hematopoiesis.

Animals↗
PubMed1998

Impact of protein malnutrition on subcellular nucleic acid and protein status of brain of aluminum-exposed rats.

Nucleic acid and protein content in various cellular fractions of different regions of the brain were investigated in male albino rats following aluminum (Al) exposure (at the dose of 15% of LD50 i.p. for 28 days) on either an adequate or inadequate protein diet. It was observed that there was a decrease in homogenate DNA content in the thalamic area (Th), midbrain-hippocampal region (MH) and cerebellum (CL), but not in the cerebrum (CC) of the protein-restricted group of animals. Increased RNA content was recorded in the ribosomal and soluble fractions of CL of the adequately protein-fed animals compared to pair-fed controls. In the low-protein-fed animals, on the other hand, a decrease in RNA content was observed in the whole homogenate and nuclear fractions of CC, MH and CL, the ribosomal and soluble fractions of MH and CL, and in the mitochondrial fraction of TH. Ribonucleolytic activity was found to be increased only in the Th and CL of the adequately protein-fed group. Protein contents in the subcellular fractions of these four regions remain almost unaltered with the present dose and duration of Al-exposure; only the soluble fraction of CC and microsomal fraction of Th of the low-protein-fed group showed a significant decrease. The results of the present investigation confirm that Al has generally depressive effects on the nucleic acid metabolism of the brain and suggest that these effects are region-specific as well as dependent on dietary protein level. It is further suggested that alterations in the cellular microenvironment, caused by protein malnutrition, may play a significant role in the modification of the effects of Al in the brain.

Aluminum↗
PubMed2006

A clinoptilolite effect on cell media and the consequent effects on tumor cells in vitro.

Clinoptilolite is a nontoxic natural zeolite with properties of an ion-exchanger and adsorbent. Earlier studies showed that clinoptilolite could be an adjuvant in cancer therapy. The aim of this study was to define effects of clinoptilolite in cell media on cell viability and activity of key proteins regulating cell survival, cell division and stress response. The number of viable cells, DNA synthesis and activity of EGF-R, PKB/Akt and NF?B was reduced, while apoptosis was increased in cells that were cultured in medium supplemneted with clinoptilolite. These results might be due to adsorbtion of some serum components such as EGF to clinoptilolite. In treated medium without serum the predominant role of clinoptilolite is that of cation exchange, likely affecting calcium levels and calcium-dependent signalling pathways. These results are in line with other data that confirm enhanced apoptosis in cells incubated in treated medium. Together, data presented here demonstrate that clinoptilolite affects cellular microenvironment through mechanisms that are dependent on adsorptive and ion-exchange characteristics of this material.

Animals↗
PubMed2003

Analysis of gene expression profile of pancreatic carcinoma using cDNA microarray.

AIM: To identify new diagnostic markers and drug targets, the gene expression profiles of pancreatic cancer were compared with that of adjacent normal tissues utilizing cDNA microarray analysis. METHODS: cDNA probes were prepared by labeling mRNA from samples of six pancreatic carcinoma tissues with Cy5-dUTP and mRNA from adjacent normal tissues with Cy3-dUTP respectively through reverse transcription. The mixed probes of each sample were then hybridized with 12 800 cDNA arrays (12 648 unique human cDNA sequences), and the fluorescent signals were scanned by ScanArray 3 000 scanner (General Scanning, Inc.). The values of Cy5-dUTP and Cy3-dUTP on each spot were analyzed and calculated by ImaGene 3.0 software (BioDiscovery, Inc.). Differentially expressed genes were screened according to the criterion that the absolute value of natural logarithm of the ratio of Cy5-dUTP to Cy3-dUTP was greater-than 0.69. RESULTS: Among 6 samples investigated, 301 genes, which accounted for 2.38 % of genes on the microarry slides, exhibited differentially expression at least in 5. There were 166 over-expressed genes including 136 having been registered in Genebank, and 135 under-expressed genes including 79 in Genebank in cancerous tissues. CONCLUSION: Microarray analysis may provide invaluable information on disease pathology, progression, resistance to treatment, and response to cellular microenvironments of pancreatic carcinoma and ultimately may lead to improving early diagnosis and discovering innovative therapeutic approaches for cancer.

Biomarkers, Tumor↗