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PubMed1988

The influence of the microenvironment of liver-specific tumor cell colonization in a murine tumor model.

UNLABELLED: Malignant tumors often show an organ-specific metastatic spread. Some cells of the primary apparently bear an affinity for growing in the microenvironment of certain organs. After i.v. injection of myofibrosarcoma cells from the primary ER 15-P into the tail vein of male C57/Bl6J mice, metastases developed in various organs. A tumor cell line (ER 15-Me3) isolated from liver metastases of the primary was found to colonize preferentially to the liver. To find out whether the liver specificity of the tumor cell line ER 15-Me3 depended on the hepatic microenvironment, tumor cells from this line were transplanted i.m. into the thighs of mice once (ER 15-Me3 i.m.1) or 5 times (ER 15-Me3 i.m.5), and then injected into the tail vein of mice. A part of the 5-times passaged tumor cell line was also injected into the mesenteric vein (ER 15-Me3 i.m.5-Me1) prior to reinjection into the tail vein. RESULTS: After i.v. administration of tumor cells from the first i.m. passage of the tumor cell line (ER 15-Me3 i.m.1) into the tail vein, the liver-specific metastatic behavior of tumor cells remained stable. Following the i.v. injection of tumor cells from the 5th i.m. transplant generation of the tumor cell line (ER 15-Me3 i.m.5) into the tail vein, organ distribution was similar to that of the primary. After only 1 mesenteric vein passage of the 5-times i.m. transplanted line ER 15-Me3 i.m.5-Me1 followed by i.v. injection into the tail vein, did tumor cells regain their liver-specific colonizing potential. Thus, the liver-specific tumor cell line seems to contain a small number of other tumor cell populations from the unselected primary. In the muscle, these tumor cells have a growth advantage over the liver-specific cells, while the latter will grow better in the liver. This indicates that the microenvironment may be one important factor influencing the organ-specific metastatic pattern of tumor cells.

Animals↗
PubMed1979

Chemical and physical microenvironments at the Viking landing sites.

Physical and chemical considerations permit the division of the near-surface regolith on Mars into at least six zones of distinct microenvironments. The zones are euphotic, duricrust/peds, tempofrost, permafrost, endolithic, and interfacial/transitional. Microenvironments vary significantly in temperature extremes, mean temperature, salt content, relative pressure of water vapor, UV and visible light irradiance, and exposure to ionizing radiation events (100 Mrad) and oxidative molecular species. From what is known of the chemistry of the atmosphere and regolith fines (soil), limits upon the aqueous chemistry of soil pastes may be estimated. Heat of wetting could reach 45 cal/g dry soil; initial pH is indeterminate between 1 and 10; ionic strength and salinity are predicted to be extremely high; freezing point depression is inadequate to provide quantities of liquid water except in special cases. The prospects for biotic survival are grim by terrestrial standards, but the extremes of biological resiliency are inaccessible to evaluation. Second-generation in situ experiments which will better define Martian microenvironments are clearly possible. Antarctic dry valleys are approximations to Martian conditions, but deviate significantly by at least half-a-dozen criteria.

Chemical Phenomena↗
PubMed2006

Distribution of extensive nifH gene diversity across physical soil microenvironments.

The diversity of nitrogen-fixing bacteria is well described for aquatic environments; however, terrestrial analyses remain mostly biased to rhizobial plant-microbe associations. We maximized the level of resolution for this study through the use of nucleotide sequence information extracted from a series of soil microenvironments, ranging from macroaggregates at 2000 microm to the clay fraction at < 75 microm in diameter. In addition, we attempted to create an overview of the distribution of terrestrial nitrogen fixers across such microenvironments by combining culture-independent techniques with a suite of natural soil environments from uniquely different origins. Soil diazotroph diversity was analyzed phylogenetically for 600 terrestrial nifH sequences from 12 midsized clone libraries based on microenvironments of three separate soils across a global scale. Statistical analyses of nifH gene clone libraries were used to estimate coverage, establish degrees of sequence overlap, and compare cluster distributions. These analyses revealed an extensive diversity in a tropical (19 phylotypes) and an arctic soil (17 phylotypes), and moderate diversity in a temperate soil (11 phylotypes). Within each soil, comparisons across aggregate size fractions delineated nifH gene cluster shifts within populations and degrees of sequence overlap that ranged from significantly different (arctic, tropical) to significantly similar (temperate). We suggest that this is due to population separation across aggregates of different size classes, which results from differences in the temporal stability of aggregates as niches for microbial communities. This study not only provides new knowledge of the arrangement of diazotrophic communities at the soil microscale, but it also contributes to the underrepresented knowledge of soil nifH sequences in the public databases.

Bacteria↗
PubMed2001

Influence of the microenvironment on invasiveness of human bladder carcinoma cell lines.

To investigate the importance of the microenvironment in bladder cancer invasion, a panel of six bladder carcinoma cell lines (SD, RT112, JON, 1207, T24, and J82) was tested in both in vitro and in vivo invasion assays. Furthermore, invasiveness was correlated with the expression of components of the E-cadherin-catenin complex. The E-cadherin-negative cell lines, T24 and J82, displayed a high in vitro invasive capacity, whereas the E-cadherin-positive cell lines, SD and JON, completely lacked in vitro invasive capacity. In contrast, in vivo invasion was noted for all cell lines, with the exception of cell line JON. Most notably, SD formed highly invasive tumors in vivo. The in vivo invasiveness of the E-cadherin-positive bladder carcinoma cell lines was associated with a heterogeneous expression of the E-cadherin-catenin complex. The discrepancy between in vitro and in vivo invasive behavior implies that, in vivo, the microenvironment plays an important role in the establishment of the invasive phenotype. In addition, it was found that orthotopic xenografting of 1207 and T24 bladder carcinoma cells resulted in site-specific tumor take and an enhanced tumor outgrowth and invasiveness, respectively, compared with heterotopic (i.e., subcutaneous) inoculation. We conclude that the site-specific growth and invasion of the bladder carcinoma cell lines in vivo and the observed assay specific invasion (in vitro vs in vivo) points to an effect of the local (bladder) microenvironment on tumor cell behavior.

Animals↗
PubMed1994

Dorsal root ganglia microenvironment of female BB Wistar diabetic rats with mild neuropathy.

Abnormalities in the microenvironment of dorsal root ganglia (DRG) might play a role in the pathogenesis of sensory abnormalities in human diabetic neuropathy. We examined aspects of DRG microenvironment by measuring local blood flow and oxygen tension in the L4 dorsal root ganglia of female BB Wistar (BBW) diabetic rats with mild neuropathy. The findings were compared with concurrent measurements of local sciatic endoneurial blood flow and oxygen tension. Diabetic rats were treated with insulin and underwent electrophysiological, blood flow and oxygen tension measurements at either 7-11 or 17-23 weeks after the development of glycosuria. Nondiabetic female BB Wistar rats from the same colony served as controls. At both ages, BBW diabetic rats had significant abnormalities in sensory, but not motor conduction compared to nondiabetic controls. Sciatic endoneurial blood flow in the diabetic rats of both ages was similar to control values, but the older (17-23 week diabetic) BBW diabetic rats had a selective reduction in DRG blood flow. Sciatic endoneurial oxygen tensions were not significantly altered in the diabetic rats. DRG oxygen tension appeared lowered in younger (7-11 week diabetic) but not older (17-23 week diabetic) BBW rats. Our findings indicate that there are important changes in the DRG microenvironment of diabetic rats with selective sensory neuropathy.

Animals↗
PubMed1991

The hematopoietic microenvironment.

Hematopoietic microenvironment is comprised of an admixture of several adherent cell types including fibroblasts, reticular adventitial cells, and marcophages. The biologic interaction of these cells with the most primitive hematopoietic progenitor cells capable of reconstituting all hematopoietic lineages within an irradiated host, as well as differentiated progenitor cells and cells of each committed lineage, has been the subject of intense investigation. Transplantation of the hematopoietic microenvironment has recently been demonstrated and this technique has been used to partially correct the microenvironmental defect in the Sl/Sld mouse. The molecular mechanism of cell surface interaction between stromal and hematopoietic stem cells is being elucidated by molecular transfection techniques in which genes for specific receptors are introduced into hematopoietic stem cell lines and then demonstrated to adhere and proliferate in contact with stromal cells expressing transfected recombinant ligands. This model has been demonstrated with the EGF receptor bearing 32D cl 3 stem cells bound to TGF alpha-producing stromal cells. Extracellular matrix components of the adherent cell layer, the binding of hematopoietic growth factor interaction with matrix components, as well as the positive and negative feedback regulatory role of hematopoietic stem cells bound to the microenvironment, represents the focus of current investigation.

Animals↗
PubMed2004

Evidence-based practice: examining the risk of toys in the microenvironment of infants in the neonatal intensive care unit.

Toys placed in the bed or microenvironment of infants in the neonatal intensive care unit (NICU) demonstrate high rates of colonization (92%). As with other fomites, toys may be one potential source of nosocomial infection (NI). This project critically evaluated the practice of placing toys in the microenvironment of critically ill infants by using the Iowa Model of Evidence-Based Practice to Promote Quality Care. With the model as a guide for decision making, the existing evidence was explored using a systematic review of the literature, case studies, scientific principles, theory, and expert opinion. A comprehensive review of the literature did not clearly identify a causal relationship between toys in the NICU microenvironment and NI. Levels of evidence suggesting an association between toys and NI were determined to be moderately strong and consistent. A plausible relationship between the practice of placing toys in the beds of NICU patients and risk for infection was found. These findings prompted a pilot practice change, eliminating toys in the NICU, to test the potential impact of this intervention. Pre- and postintervention infection rates were compared. NI rates decreased from 4.6 to 1.99 per 1,000 patient days over a 6-month evaluation period. Although this decrease was not statistically significant, it was the lowest rate recorded in 5 years. Ongoing evaluation of NI rates is in progress. Individual NICUs must determine if the evidence warrants a practice change in their setting.

Cross Infection↗
PubMed2006

Tumor microenvironment and drug resistance in hematologic malignancies.

Increasing evidence supports the role of the tumor microenvironment in conferring drug resistance as a major cause of relapse and incurability of cancers. The tumor microenvironment consists of normal stromal cells, extracellular matrix, and soluble factors such as cytokines and growth factors. Tumor-tumor cell interaction, tumor-stromal cell interaction, as well as tumor-ECM interaction, all contribute to direct cell contact mediated drug resistance. In addition, soluble factors produced in the tumor microenvironment provide further signals for tumor cell growth and survival. Environment mediated-drug resistance (EM-DR) could be considered as the totality of cell adhesion mediated drug resistance (CAM-DR) and soluble factor mediated drug resistance (SM-DR) produced by the tumor-host interaction. This review focuses on the EM-DR model system and signaling pathways involved in cell survival of hematological malignancies.

Cell Survival↗
PubMed2004

How hematopoietic stem cells know and act in cardiac microenvironment for stem cell plasticity? Impact of local renin-angiotensin systems.

Bone marrow-derived hematopoietic stem cells (HSC) can exhibit tremendous differentiation activity in numerous non-hematopoietic organs. This enigmatic process is called as 'stem cell plasticity' (SCP). HSC may promote structural and functional repair in several organs such as heart, liver, brain, and skeletal muscle via the SCP. The differentiation capacity of HSC is dependent on the specific signals present in the local tissue microenvironment. Those specific molecular signals required for the interactions of HSC and host tissues are currently unknown. The aim of this report is to propose a hypothesis on how HSC reach, recognize, and function in cardiac tissues in the context of SCP. Locally signaling cardiac microenvironment is essential for the seeding, expansion, and 'cardiomyocyte differentiation' of the HSC in the heart. Our hypothesis is that the receptors, ligands, and signaling pathways of the tissue renin-angiotensin system (RAS) serve as the link between HSC and local cardiac microenvironment in SCP. The RAS is considered as a 'tissue-based system' exhibiting paracrine functions within many organs. The presence of local hematopoietic bone marrow RAS and local cardiac RAS have been suggested. Both local tissue RASs share similar angiotensin peptide-signaling pathways such as JAK-STAT and mitogen-activated protein kinases. HSC have angiotensin type I (AT1a) receptors for the binding of angiotensin II, the active component of the RAS. Binding of angiotensin II to AT1a can increase hematopoietic progenitor cell proliferation. Local cardiac RAS has critical (patho)biological functions in the cardiomyocyte survival, renewal, and growth, as well as in cardiac remodeling. Therefore, the components of the local cardiac RAS and hematopoietic RAS could interact with each other during the SCP through myocardial tissue repair. Activation of the local myocardial RAS after injury may be related to homing and engraftment of the HSC to the cardiac tissue. Regenerating myocardial tissue may exert regulatory functions on circulating or resident HSC via the locally active RAS. Understanding the exact molecular basis of SCP in relation to local tissue RAS could offer new frontiers in the better management of ischemic cardiac diseases.

Adaptation, Physiological↗
PubMed2004

Effect of microenvironment pH of aluminum hydroxide adjuvant on the chemical stability of adsorbed antigen.

The rate of acid-catalyzed hydrolysis of glucose-1-phosphate (G1P) when adsorbed to aluminum hydroxide adjuvant was significantly slower than the rate of hydrolysis of a solution of G1P at the same pH. It was concluded that the positively charged aluminum hydroxide adjuvant (iep 11.4) electrostatically attracted anions including hydroxyls to form a double layer surrounding the adjuvant particles. Thus, the pH of the microenvironment surrounding the aluminum hydroxide adjuvant was higher than the bulk pH. Adsorbed G1P hydrolyzed at a rate associated with the pH of the microenvironment of the surface of the adjuvant rather than with the pH of the bulk solution. Comparison of the rate constant for the hydrolysis of adsorbed G1P to the pH-stability profile of G1P in solution revealed that adsorbed G1P hydrolyzed at a rate associated with a pH that was approximately two pH units higher than the bulk pH. The results suggest that the chemical stability of antigens that degrade by pH-dependent mechanisms can be optimized by modifying the surface charge of the aluminum-containing adjuvant to produce the pH of maximum stability in the microenvironment of the adjuvant.

Absorption↗
PubMed2006

Catalog of gene expression in adult neural stem cells and their in vivo microenvironment.

Stem cells generally reside in a stem cell microenvironment, where cues for self-renewal and differentiation are present. However, the genetic program underlying stem cell proliferation and multipotency is poorly understood. Transcriptome analysis of stem cells and their in vivo microenvironment is one way of uncovering the unique stemness properties and provides a framework for the elucidation of stem cell function. Here, we characterize the gene expression profile of the in vivo neural stem cell microenvironment in the lateral ventricle wall of adult mouse brain and of in vitro proliferating neural stem cells. We have also analyzed an Lhx2-expressing hematopoietic-stem-cell-like cell line in order to define the transcriptome of a well-characterized and pure cell population with stem cell characteristics. We report the generation, assembly and annotation of 50,792 high-quality 5'-end expressed sequence tag sequences. We further describe a shared expression of 1065 transcripts by all three stem cell libraries and a large overlap with previously published gene expression signatures for neural stem/progenitor cells and other multipotent stem cells. The sequences and cDNA clones obtained within this framework provide a comprehensive resource for the analysis of genes in adult stem cells that can accelerate future stem cell research.

Animals↗
PubMed2000

The mechanics of F-actin microenvironments depend on the chemistry of probing surfaces.

To understand the microscopic mechanical properties of actin networks, we monitor the motion of embedded particles with controlled surface properties. The highly resolved Brownian motions of these particles reveal the viscoelastic character of the microenvironments around them. In both non-cross-linked and highly cross-linked actin networks, particles that bind F-actin report viscoelastic moduli comparable to those determined by macroscopic rheology experiments. By contrast, particles modified to prevent actin binding have weak microenvironments that are surprisingly insensitive to the introduction of filament cross-links. Even when adjacent in the same cross-linked gel, actin-binding and nonbinding particles report viscoelastic moduli that differ by two orders of magnitude at low frequencies (0.5-1.5 rad/s) but converge at high frequencies (> 10(4) rad/s). For all particle chemistries, electron and light microscopies show no F-actin recruitment or depletion, so F-actin microheterogeneities cannot explain the deep penetration (approximately 100 nm) of nonbinding particles. Instead, we hypothesize that a local depletion of cross-linking around nonbinding particles explains the phenomena. With implications for organelle mobility in cells, our results show that actin binding is required for microenvironments to reflect macroscopic properties, and conversely, releasing actin enhances particle mobility beyond the effects of mere biochemical untethering.

Actins↗
PubMed1984

Biological functions of low-frequency vibrations (phonons). III. Helical structures and microenvironment.

Low-frequency vibrations in biomacromolecules possess significant biological functions. In this paper, the alpha-helix element is compared with a mass-distributed spring. Based on this, a set of intuitive and easily handled equations are derived for predicting the fundamental frequencies of helical structures in protein molecules. As shown in the equations, the fundamental frequency depends not only on the constituents of a helix itself but also on its microenvironment. The calculated results agree with the observations. The calculations also demonstrate that the low-frequency vibrations with wave number of approximately 30 cm-1 do not necessarily arise from motions that involve either all or very large portions of the protein molecule as previously thought; a piece of helix containing more than 10 residues and surrounded by a proper microenvironment can also generate such low-frequency motions. Furthermore , we illustrate that the low-frequency motions are closely related to the native state of a protein molecule. Upon denaturation, which is accompanied by a radical change of the relevant microenvironment, the original fundamental frequency also disappears. Consequently, this kind of special frequency termed activating low frequency can serve as a dynamic criterion in identifying whether a biomacromolecule is in its native state. The energy of a phonon excited by this kind of low-frequency vibration is of the same order of magnitude as the average enthalpy value per residue measured during conformational change in some protein molecules. Therefore, there must be some intrinsic relation between the allosteric transitions of protein molecules and their low-frequency motions.

Biophysical Phenomena↗
PubMed1996

The microenvironment influences the pattern of bacterial translocation in formula-fed neonates.

The authors previously demonstrated that neonatal rabbits fed conventional formula have a significantly greater incident of bacterial translocation than do neonatal rabbits fed breast milk. They hypothesized that exogenous bacteria in the formula and/or the microenvironment of the neonatal rabbit may contribute to the higher incidence of bacterial translocation. In the present study, the authors examined the incidence of bacterial translocation in neonatal rabbits fed pasteurized formula, unsterile formula, or breast milk while being housed in a clean or unsterile environment. The rabbits were divided into five groups. Groups I and II were fed pasteurized formula; groups III and IV were fed unsterile formula. In addition, groups I and III were housed in a clean environment, and groups II and IV were kept in an unsterile environment. The neonates in group V were fed breast milk and were kept in an unsterile environment. On the seventh day, the animals were killed, and the mesenteric lymph nodes, liver, and spleen were cultured for the presence of bacteria. Bacterial translocation occurred in 100% of group IV neonates. A clean environment (groups I and III) eliminated gram-negative bacterial translocation. A reduction (50%) in the overall incidence of bacterial translocation was obtained by pasteurizing the formula (group I v group III). Group II had significantly less gram-negative bacterial translocation than did group IV. None of the neonates in group V had translocation. The data show that a clean environment abrogates gram-negative bacterial translocation. Pasteurizing the formula significantly reduces the incidence of gram-negative bacterial translocation, and further reduces overall bacterial translocation in a clean environment. The authors hypothesize that control of the microenvironment can significantly influence the pattern of bacterial translocation in formula-fed neonates, and thus potentially reduce the incidence of gut-origin sepsis. Factors present in breast milk inhibit bacterial translocation, regardless of the microenvironment.

Animals↗
PubMed2000

Human exposure to respirable suspended particulate and airborne lead in different roadside microenvironments.

The aim of this study is to evaluate the particulate air pollution in selected roadside microenvironments of Hong Kong through an intensive field study dated from January 1997 to February 1997. The study employed the microenvironment monitoring technique to access the exposure of pedestrians to respirable suspended particulate and airborne lead (Pb) at heavily trafficked roadsides. A total of 62 roadside sites in 14 districts covering the most urbanized and densely populated areas were selected. It was found that pedestrians were exposed to a 24 h average of respirable suspended particulate, PM10, and airborne Pb (APb), typically ranged from 25.56 to 337.40 microg/m3 and 70.71 to 285.71 ng/m3, respectively. The average PM10 concentrations at different roadside microenvironments corresponding to urban residential, urban commercial, urban industrial and new town areas were 91.84, 129.08, 83.83, and 118.89 microg/m3 respectively. The corresponding values for APb were 130.01, 143.40, 127.40 and 173.17 ng/m3, respectively. It was found that measurement at EPD nearby rooftop monitoring stations might not reflect the actual roadside PM10 exposure. Most APb field study data was significantly higher than the nearby fixed station data.

Air Pollutants↗
PubMed1984

The human thymic microenvironment.

Several major points should be emphasized that provide directions for future research. First, using monoclonal reagents we have been able to phenotypically identify four major regions of the human thymus microenvironment: the thymic capsule, interlobular septae and stroma (TE-7+), the subcapsular cortex (TE-4+, Thy-1+, A2B5+, anti-p19+, BB TECS+, TE-3+), the cortex (TE-3+), and the medulla (TE-4+, A2B5+, anti-p19+, BB TECS+). TE-4+ and TE-3+ thymic epithelium constitute HLA+, Ia+ subsets of thymic epithelium that are candidates for cell types of the human thymic microenvironment that might participate in conferring MHC restriction to maturing T lymphocytes. TE-7+ stroma most likely represents the mesodermal-derived thymic component that early in development induces thymic epithelial differentiation. Second, whereas TE-4, anti-p19, and BB TECS antibodies may be thymic epithelial lineage markers, they all react with the basal layer of squamous epithelium of various organs. In particular, in the tonsil, A2B5+, TE-4+ epithelium splays out in the base of tonsillar crypts and morphologically appears similar to thymic medullary epithelial cells. Therefore, these markers of endocrine thymic epithelium may also identify extrathymic areas of T cell differentiation. Third, the concept that thymic epithelium is constantly differentiating in the developed thymus is suggested by the coexpression of TE-4, TE-8, TE-16, and TE-15 antigen by layers of squamous epithelial keratinocytes and by thymic epithelium. That there is a TE-4/TE-8/TE-15 keratinocyte maturation pathway in skin gives credence to the notion that a similar pathway exists from TE-4+, TE-8-, TE-15- endocrine medullary epithelial cells to TE-4-, TE-8+, TE-15+ Hassall's bodies. Fourth, from the literature and the work presented in this review, three phases of thymic microenvironment development can be defined. The first phase is during early fetal development (4 to 8 weeks in humans) when mesodermal-derived fibrous tissue induces endodermal and ectodermal-derived thymic epithelium to proliferate and mature. TE-7+ mesenchymal stroma invaginates TE-4+ thymic epithelium and effects thymic lobulation. The second phase occurs between 9 and 15 weeks fetal development when the thymic primordia is colonized by blood-borne thymocyte precursors. Presumably during this stage, thymic epithelium promotes bone marrow cell colonization of thymus by producing chemoattractant molecules.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2001

The microenvironment of immobilized Arg-Gly-Asp peptides is an important determinant of cell adhesion.

This paper uses self-assembled monolayers on gold as a model system to demonstrate that the attachment and spreading of Swiss 3T3 fibroblasts depends strongly on the microenvironment of immobilized RGD peptides. This work utilized monolayers that present mixtures of Arg-Gly-Asp peptides, which are ligands for cellular integrin receptors, and oligo(ethylene glycol) groups, which resist the nonspecific adsorption of protein. The microenvironment of the peptide ligands was controlled by altering the length of the surrounding oligo(ethylene glycol) groups on the monolayer. By using thiols that present either tri-, tetra-, penta-, or hexa(ethylene glycol) units, the average distance separating the glycol groups and the peptide ligand is altered while the structure and properties of the background remain unchanged. Cell attachment to monolayers presenting a fixed density of peptide decreased as the length of the oligo(ethylene glycol) group increased. The average projected area of attached cells showed a similar trend. At lower densities of immobilized peptide, decreases in both cell attachment and projected cell area were more pronounced. Attachment and spreading did not depend on density of peptide on monolayers presenting tri(ethylene glycol) groups, but showed a high sensitivity to density of ligand on monolayers presenting longer glycol oligomers. Experiments that used a soluble peptide to inhibit the attachment of cells to monolayers demonstrated that the strength of the cell-substrate interaction decreased on monolayers presenting longer glycol groups. Together, these results suggest that the microenvironment of the peptide ligand influences the affinity of the integrin-peptide interaction and that weaker interactions display a density-dependent enhancement of binding during cell attachment and spreading. This finding is an important consideration in studies that correlate biological function with the composition of ligands on a substrate. This finding also represents an important principle for the design of biologically active materials because it illustrates the degree to which the presentation of adhesion motifs can modify the response of mammalian cells.

3T3 Cells↗
PubMed2002

In vitro characterization of hematopoietic microenvironment cells from patients with myelodysplastic syndrome.

In vitro studies on the functional integrity of the hematopoietic microenvironment in myelodysplasia have been controversial. Although some of them suggest that such a microenvironment is functionally normal, there is increasing evidence indicating that there are alterations in the function of microenvironment (adherent) cell layers from myelodysplastic syndromes (MDS) marrow. Adherent cell layers developed in vitro, however, consist of a mixture of different cell types-mostly fibroblasts and macrophages-thus, it is not clear which cell type(s) is(are) functionally abnormal in this disorder. In order to address this issue, in the present study, we first assessed some functional properties of MDS-derived adherent cell layers, as a whole, and then we analyzed those same functional properties after separating these cells into two different populations: a fibroblast-enriched cell layer and a macrophage-enriched cell layer. When whole adherent layers from MDS patients were analyzed, no significant differences were observed, as compared to their normal counterparts, in terms of morphology and total cell number. A major difference, however, was observed when analyzing the production of the cytokines interleukin-6 (IL-6) and tumor necrosis factor (TNF-alpha). Indeed, adherent layers from MDS patients produced higher levels of these cytokines (2- and 22-fold, respectively), as compared to normal layers. When fibroblast- and macrophage-enriched cell layers were analyzed, a higher apoptotic index was observed in those derived from MDS marrow (4% of TUNEL-positive cells in normal fibroblast layers versus 27% in MDS-derived fibroblast layers; 7% of TUNEL-positive cells in normal macrophage layers versus 24% in MDS macrophage layers). Macrophages from MDS marrow produced significantly higher levels of TNF-alpha (nine-fold) than their normal counterparts. MDS-derived fibroblasts, on the other hand, produced higher levels of IL-6 (nine-fold), as compared to normal fibroblasts. Surprisingly, whereas normal fibroblasts showed a discrete production of TNF-alpha, we found a very high production of this cytokine in cultures of fibroblasts from MDS patients. In summary, in the present study we have demonstrated that, at least in vitro, both fibroblasts and macrophages from MDS bone marrow (BM) are functionally abnormal. Such abnormalities include an increased apoptotic index, as well as a high production of both IL-6 and TNF-alpha.

Adult↗