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PubMed2006

Osteoblasts provide a suitable microenvironment for the action of receptor activator of nuclear factor-kappaB ligand.

Deficiency of osteoprotegerin (OPG), a soluble decoy receptor for receptor activator of nuclear factor-kappaB ligand (RANKL), in mice induces osteoporosis caused by enhanced bone resorption. Serum concentrations of RANKL are extremely high in OPG-deficient (OPG(-/-)) mice, suggesting that circulating RANKL is involved in osteoclastogenesis. RANKL(-/-) mice exhibit osteopetrosis, with the absence of osteoclasts. We examined the requirements for osteoclastogenesis using OPG(-/-) mice, RANKL(-/-) mice, and a system involving bone morphogenetic protein 2 (BMP-2)-induced ectopic bone formation. When collagen disks containing BMP-2 (BMP-2-disks) or vehicle were implanted into OPG(-/-) mice, osteoclast-like cells (OCLs) and alkaline phosphatase-positive OCLs appeared in BMP-2-disks but not the control disks. F4/80-positive osteoclast precursors were similarly distributed in both BMP-2- and control disks. Cells expressing RANKL were detected in the BMP-2-disks, and the addition of OPG to the disk inhibited OCL formation. Muscle cells in culture differentiated into alkaline phosphatase-positive cells in the presence of BMP-2 and accordingly expressed RANKL mRNA in response to PTH. This suggests that RANKL expressed by osteoblasts is a requirement for osteoclastogenesis. We then examined how osteoblasts are involved in osteoclastogenesis other than RANKL expression, using RANKL(-/-) mice. BMP-2- and control disks were implanted into RANKL(-/-) mice, which were injected with RANKL for 7 d. Many OCLs were observed in the BMP-2-disks and bone tissues but not the control disks. These results suggest that osteoblasts also play important roles in osteoclastogenesis through offering the critical microenvironment for the action of RANKL.

Animals↗
PubMed1991

Deficiency of osteoclasts in osteopetrotic mice is due to a defect in the local microenvironment provided by osteoblastic cells.

We have reported that osteoblastic cells are required for differentiation of osteoclast progenitors in splenic tissues into multinucleated osteoclasts. In the present study we examined the pathogenesis of the osteoclast deficiency in osteopetrotic (op/op) mice using a coculture system of spleen cells and osteoblastic cells. When spleen cells obtained from op/op or normal (+/?) littermates of op/+ parent mice were cocultured with osteoblastic cells obtained from calvaria of normal ddy strain mice, numerous tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells (MNCs) were formed in the presence of 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3]. Most of the TRAP-positive MNCs bound [125I]salmon calcitonin. This suggests that there is no abnormality in the osteoclast progenitors present in the splenic tissues of op/op mice. When osteoblastic cells from +/? littermates were cocultured with normal spleen cells from ddy mice, TRAP-positive MNCs were similarly formed in response to 1 alpha,25(OH)2D3. In contrast, in cocultures of op/op osteoblastic cells with normal spleen cells, no TRAP-positive cells appeared, even in the presence of 1 alpha,25(OH)2D3. The op/op mutation was recently reported to exist in the coding region of the macrophage colony-stimulating factor (M-CSF) gene. Adding M-CSF and 1 alpha,25(OH)2D3 to the coculture with op/op osteoblastic cells induced the appearance of TRAP-positive MNCs with calcitonin receptors. These results clearly indicate that osteoclast deficiency in op/op mice is due to a defect in the local microenvironment in bone, in which M-CSF produced by osteoblastic cells plays a critical role in osteoclast development.

Acid Phosphatase↗
PubMed2002

The influence of aggregate microenvironment on the dissolution of oxazepam in ternary surfactant interactive mixtures.

The purpose of this research was to test the hypothesis that the dissolution rate of oxazepam in interactive mixtures was dependent on the influence of surfactant within the microenvironment of mixed oxazepam-surfactant aggegrates produced during dissolution. The studies utilised both powder and intrinsic dissolution methodology; spectrophotometric assays were developed and validated and dissolution data were modelled using multi-exponential equations and dissolution rate constants estimated using non-linear least squares algorithms. For a series of water-soluble ternary additives to the oxazepam interactive mixture, sodium lauryl sulfate and cetrimide were shown not only to decrease aggregation through enhanced dispersion, but also to increase the dissolution rate constant. Such an increase in dissolution rate constant was observed in the intrinsic dissolution studies when surfactant concentrations exceeded the critical micelle concentration and the oxazepam solubility increased. Laser diffraction particle sizing during the dissolution process confirmed the presence of dispersed particles and aggregates and demonstrated that the presence of surfactant improved the state of dispersion. The results of studies using different rotational speeds produced unexpected increases in aggregation and decreases in dissolution rate constants at about 150 rev min(-1), consistent with the transient formation of loose aggregates containing dissolved surfactant.

Linear Models↗
PubMed2003

Evidence that Myc activation depletes the epidermal stem cell compartment by modulating adhesive interactions with the local microenvironment.

Activation of Myc (c-Myc) causes epidermal cells to exit the stem cell compartment and differentiate into sebocytes and interfollicular epidermis at the expense of the hair lineages. To investigate how Myc exerts these effects we analysed the transcription of more than 10000 genes following Myc activation in the basal layer of mouse epidermis for 1 or 4 days. The major classes of induced genes were involved in synthesis and processing of RNA and proteins, in cell proliferation and in differentiation. More than 40% of the downregulated genes encoded cell adhesion and cytoskeleton proteins. Repression of these genes resulted in profound changes in the adhesive and motile behaviour of keratinocytes. Myc activation inhibited cell motility and wound healing, correlating with decreased expression of a large number of extracellular matrix proteins. Cell adhesion and spreading were also impaired, and this correlated with decreased expression of the alpha6beta4 integrin, decreased formation of hemidesmosomes and decreased assembly of the actomyosin cytoskeleton. We propose that Myc stimulates exit from the stem cell compartment by reducing adhesive interactions with the local microenvironment or niche, and that the failure of hair differentiation reflects an inability of keratinocytes to migrate along the outer root sheath to receive hair inductive stimuli.

Animals↗
PubMed1990

Microenvironment created by stromal cells is essential for a rapid expansion of erythroid cells in mouse fetal liver.

Mouse stromal cell lines (FLS lines), established from the livers of 13-day gestation mouse fetus, supported the proliferation and differentiation of the erythroid progenitor cells from mouse fetal livers and bone marrow in a semisolid medium in the presence of erythropoietin. A large erythroid colony of over 1000 benzidine-positive erythroid cells was developed from a single erythroid progenitor cell on the FLS cell layer after 4 days of culture. When in close contact with the layer, the erythroid progenitor cells divided rapidly with an average generation time of 9.6 h and mature erythroid cells, including enucleated erythrocytes, were produced. The present studies demonstrate that the microenvironment created by the stromal cells can support the rapid expansion of erythropoietic cell population in the fetal liver of mice.

Animals↗
PubMed2005

Stimulatory effects of a three-dimensional microenvironment on cell-mediated fibronectin fibrillogenesis.

The assembly of fibronectin into a fibrillar matrix is a regulated step-wise process that involves binding to integrin receptors and interactions between fibronectin molecules. This process has been studied extensively using cells in two-dimensional (2D) monolayer culture. In most situations in vivo, however, matrix assembly occurs within existing three-dimensional (3D) extracellular matrix networks. In an attempt to mimic this environment, we analyzed matrix assembly by fibroblasts cultured on a pre-assembled 3D fibronectin matrix and found significant stimulation of fibronectin fibril assembly compared to cells in 2D culture. Lower amounts of fibronectin were needed to initiate the assembly process, fibrils accumulated to higher density, and the 3D fibril organization played a key role in the stimulatory effect. Moreover, cells expressing activation-dependent integrins were able to assemble fibronectin matrix without exogenous stimulation, suggesting regulatory effects of the 3D fibronectin matrix on integrin activity. These results provide evidence for an additional level of control of fibronectin deposition through cell interactions with the local microenvironment.

Animals↗
PubMed2001

Detection of Cl- flux in the apical microenvironment of cultured foetal distal lung epithelial cells.

A self-referencing Cl--selective microelectrode (Cl- SrE) was developed and used to detect changes in the direction and magnitude of the Cl- flux (J(Cl)) from the apical region of cultured foetal distal lung epithelial cells (FDLEs) as a function of external Cl- concentration ([Cl-]e) and in response to pharmacological challenges. The technique, which is similar to that developed for other ion-selective microelectrodes, centres on the oscillation of a Cl--selective microelectrode between known points, micrometres apart, orthogonal to the plasma membrane. Application of the Fick principle to the differential voltage obtained per excursion amplitude (the referenced signal) yields the Cl- flux (pmol x cm(-2) x s(-1)). A Cl- effusion gradient was used to confirm that empirical measurements of J(Cl) using the Cl- SrE were statistically similar to predicted flux values calculated from the fall in [Cl-] with distance from the tip of the effusion source. Apical J(Cl) was then measured as a function of [Cl-]e from polarised FDLE cultures grown on permeable supports. At [Cl-]e<50 mmol x l(-1), an apical-to-basolateral (inward) flux, maximal at 400 pmol x cm(-2 ) x s(-1), was observed; this reverted to a continuous basolateral-to-apical (outward) flux of 203 pmol x cm(-2 ) x s(-1) at [Cl]e>100 mmol x l(-1). At [Cl-]e>100 mmol x l(-1), isoproterenol (basolaterally applied, 10 micromol x l(-1)) activated a Cl- influx of 561 pmol x cm(-2 ) x s(-1), whereas UTP (apically applied, 100 micromol x l(-1)) stimulated a Cl- efflux of 300 pmol x cm(-2) x s(-1). In all cases, 50-70 % of J(Cl) was abolished by Cl- channel blockade using 10 micromol x l(-1) diphenylamine-2-carboxylic acid (DPC) or 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB). We conclude that the Cl- SrE resolves a Cl- gradient in the microenvironment of the apical region of lung epithelia that varies in both direction and magnitude as a function of external [Cl-]e and in response to Cl- channel blockade and to beta2 adrenoreceptor and P2Y receptor agonists.

Adrenergic beta-Agonists↗
PubMed2004

Aminopeptidase N/CD13 regulates the fetal liver microenvironment of hematopoiesis.

Fetal liver (FL) hematopoiesis is thought to be important for expanding the cell number during ontogeny. In order to investigate the cellular interaction molecules among FL stromal and hematopoietic cells, we established a monoclonal antibody, Ndk-10, that reacts with FL stromal cells but not with dish non-adherent cells. When Ndk-10 was added to an FL stromal and hematopoietic cell-coculture, it inhibited the survival of c-kit+ cells. The inhibitory activity of Ndk-10 was also observed in the fetal liver organ culture. The Ndk-10 recognized a 150 kD molecule in the adherent cells of FL and kidney, and the N-terminal amino acid sequence was identical to that of mouse aminopeptidase N/CD13. The peptidase activity of CD13 was inhibited by Ndk-10, and addition of its specific inhibitor resulted in the same inhibitory activity as Ndk-10. We propose that aminopeptidase N/CD13 is a critical molecule that regulates the survival of c-kit+ cells in the FL microenvironment.

Animals↗
PubMed1983

Differences in the microenvironment of a polycarbonate caging system: bedding vs raised wire floors.

The microenvironment of polycarbonate cages housing rats with and without various types of bedding was compared with that of cages that utilized wire floor inserts with different bedding types. Parameters monitored were temperature, humidity, ammonia concentrations and particulates. No differences were noted in the various caging types in relation to temperature and humidity measurements. Significant differences in ammonia concentrations existed in some of the cages when bedding material was used. The use of raised floorwalk inserts also demonstrated significant differences in particulate counts to cages without inserts. The data obtained demonstrated that contact bedding was useful in controlling ammonia generation and that a raised floorwalk insert reduced significantly the aerosolization of bedding particles that could be ingested or inhaled by the rats.

Ammonia↗
PubMed2002

Studies of certain factors affecting the microenvironment and microflora of the external ear of the dog in health and disease.

A total of 187 dogs, 110 with clinical signs of otitis externa (OE), and 77 without history or clinical signs of OE, were examined microenvironment and microbiological analysis of their ear exudates made. The aural temperature and humidity of 160 dogs were measured. There were no significant difference between healthy dogs and OE dogs. German shepherd showed relatively lower temperature (p<0.01) and higher humidity (p<0.01). The mean log(10) number of microbial organisms of ears of OE dogs (4.16 +/- 0.31 cfu/g) was significantly increased, compared to that from the ears of non-OE group (2.55 +/- 0.24 cfu/g). Pseudomonas spp. and Proteus spp. were detected only from OE dogs. In addition, three enterotoxigenic Staphylococcus aureus were isolated from ear specimens.

Animals↗
PubMed2002

Role of the bone marrow microenvironment in multiple myeloma.

On June 26-27, 2001, the Sixth Research Roundtable in Multiple Myeloma, entitled "The Role of the Bone Microenvironment in Multiple Myeloma," was held and focused on the biology of cell-to-cell interactions, the mediators of bone disease, and novel treatment strategies for myeloma. Studies on cell-cell interactions showed that vascular cell adhesion molecule 1, expressed by local endothelial and stromal cells, binds to tumor cell surface integrins in which expression may be increased by tumor cell-derived chemokines such as macrophage inflammatory protein (MIP) 1alpha. These adhesive interactions increase production and release of vascular endothelial growth factor (VEGF). Studies on myeloma bone disease showed the ligand for receptor activator of nuclear transcription factor-kappaB (RANKL) was expressed on tumor cells and stromal cells associated with myeloma cells and was critical for osteoclast-induced osteolysis. Blockade of RANKL suppressed osteoclast maturation, bone resorption, and tumor development. Bisphosphonates, in addition to reducing osteoclast mobility and inducing osteoclast apoptosis, also decreased tumor cell adhesion to stroma. Immunomodulatory drugs such as thalidomide analogues targeted these tumor cell-stromal cell interactions, blocking both secretion of cytokines and activation of intracellular signaling pathways required for tumor survival and growth. These agents induced tumor cell apoptosis, decreased neovascularization, and potentiated natural killer cell activity. The proteasome inhibitor PS-341 also prevented expression of adhesion molecules and cytokines and triggered tumor cell apoptosis, even in drug-resistant cell lines, while showing minimal activity in healthy cells. In addition, potential therapeutic agents under investigation, which included RANKL antagonists, protein prenylation inhibitors, and osteoblast growth factors, were discussed.

Adjuvants, Immunologic↗
PubMed2005

Generation of murine stromal cell lines: models for the microenvironment of the embryonic mouse aorta-gonads-mesonephros region.

We describe a method to derive cell lines and clones from cells of the murine midgestation aorta-gonads-mesonephros (AGM) microenvironment. We start from subdissected AGM regions in "explant-" or "single-cell suspension"-type cultures from embryos transgenic for tsA58, a temperature-sensitive mutant of the SV40 T antigen gene. The number of cells in such cultures initially expand, but in most cases, this expansion phase is followed by a stable or even decline in cell number. After this so-called crisis phase, cell proliferation is noticeable in more than 90% of the cultures. Stromal cell clones can be isolated from these cultures, some of which have been cultured for more than 50 population doublings. These stromal cell clones are valuable tools for the study of the regulation of hematopoietic stem and progenitor cells in the midgestation mouse embryo.

Animals↗
PubMed2006

A novel experimental platform for investigating cancer growth and anti-cancer therapy in a human tissue microenvironment derived from human embryonic stem cells.

There is no available experimental system wherein human cancer cells can be grown in the context of a mixed population of normal differentiated human cells for testing biological aspects of cancer cell growth (tumor cell invasion, angiogenesis) or response to anti-cancer therapies. Human embryonic stem cells when implanted into immunocompromised mice develop teratomas containing complex structures, comprising differentiated cell types representing the major germline-derived lineages. We sought to determine whether human cancer cells would grow within such teratomas and display properties associated with malignancy such as invasiveness and recruitment of blood vessels. Ovarian cancer cells (HEY), stably expressing an H2A-GFP fusion protein, which allows tracking of tumor cells, were injected into mature teratomas and developed into tumors. The growth, proliferation capacity, invasion, and induction of blood vessel formation were examined. We propose using the novel experimental platform we have described, consisting of human tumor cells growing within a human cellular microenvironment derived from human embryonic stem cells, to develop a preclinical model for investigating and manipulating the stromal response in tumor cell growth, as an additional tool in cancer research.

Animals↗
PubMed2005

The role of the bone marrow microenvironment in multiple myeloma.

Multiple myeloma (MM) is a malignant disease that results from an excess of monotypic plasma cells in the bone marrow (BM). This malignancy is characterised by complex karyotypic aberrancies. In 60% of all MM there are recurrent primary translocations involving the heavy chain gene locus. The MM cells strongly interact with the BM microenvironment, which is composed of endothelial cells, stromal cells, osteoclasts, osteoblasts, immune cells, fat cells and the extracellular matrix. This interaction is responsible for the specific homing in the BM, the proliferation and survival of the MM cells, the resistance of MM cells to chemotherapy, the development of osteolysis, immunodeficiency and anaemia. New therapeutic agents target both the MM, as well as the interaction MM cell - BM microenviroment.

Animals↗
PubMed2001

Histamine dihydrochloride: inhibiting oxidants and synergising IL-2-mediated immune activation in the tumour microenvironment.

The potential role of histamine in cancer immunotherapy has been a subject of interest for more than a decade. A significant body of research has elucidated the action of histamine in a model system that mimics the tumour microenvironment. In vitro evidence indicates that histamine inhibits the generation and release of reactive oxygen species (ROS) by monocytes/macrophages (MO) during respiratory burst. Since ROS have been shown to abrogate peritumoural and intratumoural cytokine activation of natural killer (NK) and T-cells and induce apoptosis of these cells in vitro, inhibition of ROS may enable cytokines to activate NK and T-cells and restore their antineoplastic, cytotoxic capabilities. Experimental data indicate that histamine and interleukin-2 (IL-2) act synergistically to activate NK cell cytotoxicity (NKCC). Although IL-2, a regulator of immune responses, has been shown to promote NKCC in monotherapy for metastatic melanoma (MM), renal cell carcinoma (RCC) and acute myeloid leukaemia (AML), objective responses occur in a minority of patients and survival is not significantly extended, except for a minority of patients with MM using high-dose regimens which have not been widely adopted. In vitro findings suggest that the addition of histamine to IL-2 therapy might improve response rates and disease-free survival by protecting the cells of the immune system from oxidative stress and inducing natural endogenous immune cytotoxicity. An IL-2/histamine Phase III trial is in progress in a population of AML patients. A recently completed Phase III trial of IL-2 vs. IL-2/histamine in patients with MM demonstrated a trend towards a superior survival benefit from IL-2/histamine for all patients entered, and a statistically significant survival benefit for patients with hepatic metastases.

Animals↗
PubMed2004

Influence of sleep position experience on ability of prone-sleeping infants to escape from asphyxiating microenvironments by changing head position.

OBJECTIVE: Several studies have found that back- or side-sleeping infants who are inexperienced in prone sleeping are at much higher risk for sudden infant death syndrome (SIDS) when they turn to prone or are placed prone for sleep compared with infants who normally sleep prone. Moreover, such inexperienced infants are more likely to be found in the face-down position at death after being placed prone compared with SIDS infants who are experienced in prone sleeping. We hypothesized that lack of experience in prone sleeping is associated with increased difficulty in changing head position to avoid an asphyxiating sleep environment. METHODS: We studied 38 healthy infants while they slept prone. Half of these were experienced and half were inexperienced in prone sleeping. To create a mildly asphyxiating microenvironment, we placed infants to sleep prone with their faces covered by soft bedding. We recorded inspired CO2 (CO2I), electrocardiogram, and respiration, and we videotaped head movements. Also, we assessed gross motor development (Denver Development Scale). RESULTS: When sleeping prone, with their faces covered by bedding, all infants experienced mild asphyxia as a result of rebreathing. All aroused and attempted escape from this environment. Infants used 3 stereotyped head-repositioning strategies. The least effective was nuzzling into the bedding with occasional brief head lifts. More effective were head lifts combined with a head turn. Some infants, however, could turn only to 1 side, right or left. Infants who were inexperienced in prone sleeping had less effective protective behaviors than experienced infants. Infant age did not correlate with efficacy of protective behaviors. Infants who were experienced in prone sleep had advanced gross motor development compared with inexperienced infants. CONCLUSION: Infants who are inexperienced in prone sleeping have decreased ability to escape from asphyxiating sleep environments when placed prone. These observations potentially explain the increased risk associated with prone sleep in infants who are inexperienced. The increased occurrence of the face-down position in such infants is also potentially explained. These findings suggest that airway protective behaviors may be acquired through the mechanism of operant conditioning (learning).

Aging↗
PubMed2001

The photochemistry of flutamide and its inclusion complex with beta-cyclodextrin. Dramatic effect of the microenvironment on the nature and on the efficiency of the photodegradation pathways.

The photochemistry of the anticancer drug flutamide (FM), 2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]propanamide, in homogeneous media and in the beta-cyclodextrin (beta-CD) cavity has been investigated. The photoreactivity of the free molecule has been rationalized on the basis of an intramolecular nitro to nitrite rearrangement followed by cleavage of the nitrite intermediate. The twisted geometry of the nitro group with respect to the aromatic plane plays a key role in triggering such a photoprocess. Incorporation of FM in the beta-CD cavity leads to dramatic effects on both the efficiency and the nature of the photochemical deactivation pathways of the guest molecule. A 20-fold increase in the FM photodecomposition quantum yield and the formation of photoproducts originated by both reduction of the nitro group and cleavage of the amide bond were observed in the presence of the macrocycle. Such a behavior cannot be attributed exclusively to the micropolarity of beta-CD and/or to its role as a reactant. The induced circular dichroism spectra and the nature of the photoproducts formed in these experimental conditions provide indications that the photoreactivity in the beta-CD microenvironment could likely be mediated by structural changes of FM upon complexation.

Antineoplastic Agents, Hormonal↗
PubMed2005

Hematopoietic progenitor cells and cellular microenvironment: behavioral and molecular changes upon interaction.

Cell-cell contact between stem cells and cellular determinants of the microenvironment plays an essential role in controlling cell division. Using human hematopoietic progenitor cells (CD34+/CD38-) and a stroma cell line (AFT024) as a model, we have studied the initial behavioral and molecular sequel of this interaction. Time-lapse microscopy showed that CD34+/CD38- cells actively migrated toward and sought contact with stroma cells and 30% of them adhered firmly to AFT024 stroma through the uropod. CD44 and CD34 are colocalized at the site of contact. Gene expression profiles of CD34+/CD38- cells upon cultivation with or without stroma for 16, 20, 48, or 72 hours were analyzed using our human genome cDNA microarray. Chk1, egr1, and cxcl2 were among the first genes upregulated within 16 hours. Genes with the highest upregulation throughout the time course included tubulin genes, ezrin, c1qr1, fos, pcna, mcm6, ung, and dnmt1, genes that play an essential role in reorganization of the cytoskeleton system, stabilization of DNA, and methylation patterns. Our results demonstrate directed migration of CD34+/CD38- cells toward AFT024 and adhesion through the uropod and that upon interaction with supportive stroma, reorganization of the cytoskeleton system, regulation of cell division, and maintenance of genetic stability represent the most essential steps.

Animals↗