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PubMedDate not supplied

Tissue factory: conceptual design of a modular system for the in vitro generation of functional tissues.

Tissue factory is a modular system designed to generate artificial tissues under optimal perfusion culture conditions. The microenvironment within the culture containers can be fine-tuned to meet the physiological needs of individual tissues, so that the generation of differentiated three-dimensional tissue constructs becomes possible. An optimal physiological environment is created by modulating a liquid phase as well as an artificial interstitium surrounding the growing construct. An innovative construction principle allows production of tissue culture containers, gas exchangers, and gas expanders at minimal material expenditure. Therefore it will be possible for the first time to produce sterile one-way perfusion culture modules for the generation of artificial tissues. The modules can be used separately as well as in a combined module. The system is designed to provide a possible platform for the standardized production of artificial tissues for future applications in biomedicine.

Cell Culture Techniques↗

PubMedDate not supplied

Identification of neural crest derived cells within the cellular microenvironment of the human thymus employing a library of monoclonal antibodies raised against neuronal tissues.

The organization of optimal microenvironmental conditions within the developing thymus for lymphatic stem cell migration and their further maturation requires cellular and humoral participation of the neural crest. Recently, the immunophenotypical (IP) heterogeneity of lymphatic cells has become a scientific fact. Monoclonal antibodies (MoABs) produced against the various subpopulations of the reticulo-epithelial cells (RE) demonstrated their heterogeneity. We suggest that with a library of MoABs, raised against normal neuronal tissues, neural tumors, and a medulloblastoma cell line, including UJ13/A, UJ127.11, UJ167.11, UJ223.8, UJ308, J1153, A2B5, 215.D11, 275.G7, 282.1, antineurofilament (NF - med. m.w.), and anti-Thy-1 it is possible to recognize cells of neural crest origin within the postnatal thymic cellular microenvironment. Evidence has been collected concerning such connections between the nervous system and the thymus, such as the production of neuropeptides, oxytocin, and neurophysin by the thymus. Our immunohistochemical study was carried out on quick-frozen sections of human postnatal thymuses removed during open heart surgery, employing an indirect, alkaline phosphatase conjugated streptavidin-biotin technique. The employed MoABs reacted with the subcapsular (outer cortex) thymic nurse cells (TNCs) and with medullary RE cells, in close contact with already mature, immunocompetent T lymphocytes ready to leave the thymic microenvironment and enter the peripheral blood. The thymic medulla's strong immunoreactivity with A2B5, which binds to the GQ ganglioside, is typical for peptide secreting cells often migrated from the neural crest. A2B5+, Thy-1+ IP was demonstrated on the large TNCs. Cortical RE cells showed reactivity with UJ127.11, UJ223.8, and UJ308. Dense expression of neural crest antigens was detected in the Hassall's bodies (HBs) employing MoABs UJ223.8, UJ308, 215.D11, and 275.G7. These results suggest a neural crest origin for TNCs and for 20% to 30% of the cells of thymic microenvironment. The outer (peripheral) part of the HBs contained functionally very active RE cells. These RE cells also expressed antigens characteristic of the neural crest, detectable with MoABs UJ127.11, UJ223.8, UJ308, J1153, 215.D11, 275.G7 and A2B5.

Animals↗

PubMed1993

Altered antigen expression of microglia in the aged rodent CNS.

Microglia, the resident macrophages of the central nervous system, are characterised by a highly specialized morphology and unusual antigenic phenotype. Microglia appear to be downregulated by their microenvironment when compared to other tissue macrophages. We have studied the microglia in brains of healthy, aged rats with a panel of monoclonal antibodies. We have found that microglia in the brains of these aged rats express antigens that are downregulated or absent from microglia of juvenile rats. The stimuli which give rise to this upregulated phenotype are not known. Age related changes in the phenotype of microglia should be taken into account when considering the possible role of microglia in neuropathological conditions.

Aging↗

PubMed2003

Efficient tumor cell lysis by autologous, tumor-resident T lymphocytes in primary ovarian cancer samples by an EP-CAM-/CD3-bispecific antibody.

The epithelial cell adhesion molecule (Ep-CAM) is expressed on the surface of most human carcinomas, including ovarian, breast, lung, prostate and colorectal carcinoma. Ep-CAM was shown to be a valid target for monoclonal antibody-based therapies. We have investigated whether an Ep-CAM-/CD3-bispecific single-chain antibody called bscEp-CAM x CD3 is effective in tumor cell elimination within the cellular microenvironment of primary ovarian cancer tissue. The ex vivo elimination of ovarian cancer cells in tumor preparations from 21 patients was monitored by flow cytometry using Ep-CAM/CA-125 double-labeling or Ep-CAM single-labeling combined with propidium iodide uptake of cells. Methodology was established by the ovarian cancer cell line OvCAR. A total of 17 (81%) patient samples showed a dose-dependent tumor cell elimination by bscEp-CAM x CD3. High and specific tumor cell lysis was seen at bscEp-CAM x CD3 concentrations as low as 1 ng/ml, at very low effector:target ratios and in the absence of T cell costimulation. The high efficacy of the bispecific antibody may be due to the non-restricted activation of tumor-resident cytotoxic T lymphocytes. In clinical trials, the ex vivo data with the T cell-recruiting bispecific antibody bscEp-CAM x CD3 may translate into a high response rate and efficacy of tumor cell elimination.

Antibodies, Bispecific↗

PubMed2003

Potential of p38 MAP kinase inhibitors in the treatment of cancer.

The involvement of chronic inflammation in tumor development and progression is reviewed. Based on the natural history of certain diseases and epidemiology studies, a strong association has been established between particular chronic inflammatory conditions and eventual tumor appearance. Solid tumors require a stroma for their growth and recruit macrophages to synthesize essential growth and angiogenic factors that they do not have the capacity to produce. The microenvironment of the local host tissue appears to be an active participant in exchanging cytokines and enzymes with tumor cells that modify the local extracellular matrix, stimulate migration, and promote tumor angiogenesis, proliferation and survival. The role of p38 MAP kinase as a therapeutic target for treating cancer is discussed.

Angiogenesis Inhibitors↗

PubMed1996

Expression of stem-cell factor and its receptor c-kit protein in normal testicular tissue and malignant germ-cell tumours.

The proto-oncogene c-kit and its ligand stem-cell factor (SCF) may play an important role in the development of normal and malignant testicular tissue. This study investigates the presence of SCF and c-kit protein in 32 orchiectomy specimens of patients with testicular cancer, in 5 specimens of normal testicular tissue and in three established non-seminomatous germ-cell cancer cell lines (H12.1, H32, 577ML) by an immunohistochemical approach. Out of 9 testicular cancer specimens classified as pure seminomas, 7 (78%) showed a strong immunohistochemical reaction for both SCF and c-kit protein on the surface of the tumour cells. Fourteen non-seminomatous germ-cell tumours composed of embryonal carcinoma were completely negative for both SCF and c-kit proteins and only faint positivity was found in 6 tumours (26%). Differentiated teratomatous structures within the specimens on non-seminomatous tumours showed a strong immunohistochemical reaction for SCF and c-kit protein in 8 of 11 (73%) cases. All three testicular cancer cell lines showed only faint staining reactions for c-kit protein and none for SCF. No secretion of SCF by the three lines in vitro was detected. The addition of high concentrations of SCF (100 ng/ml) to the testicular cancer cell lines in culture conditions without fetal calf serum resulted in a 1.4 to 3-fold growth stimulation compared to cell growth in serum-free medium alone. This effect was not detectable when the cells were cultured in serum-containing media. In the normal testicular tissue the germ-cells displayed a strong immunohistochemical reaction for c-kit protein while SCF positivity was found at the tubular membrane and on the surface of Sertoli cells. The SCF/c-kit system may possess a regulatory function in normal testicular tissue by possibly providing the microenvironment necessary for spermatogenesis. With the development of testicular cancer, this regulatory system seems to be lost, particularly in non-seminomatous germ-cell tumours. A growth-stimulatory effect of high concentrations of SCF on non-seminomatous testicular cancer cell lines can be detected only in culture conditions with serum-free media. The effects achievable by the combination of SCF with other growth factors need to be further studied, as well as the role of the c-kit/SCF regulatory system for normal spermatogenesis and its possible implications for the understanding and treatment of male infertility.

Germinoma↗

PubMed1992

Induction of interdigitating reticulum cell-like differentiation in human monocytic leukemia cells by conditioned medium from IL-2-stimulated helper T-cells.

Monocytic leukemia (MoL) cells were obtained from the peripheral blood of a patient in whom the leukemic cells infiltrating various lymphoreticular organs exhibited features intermediate between interdigitating reticulum cells (IDC) and ordinary phagocytic macrophages, whereas the leukemic cells in the peripheral blood were essentially monocytic and lacked such features. Peripheral blood CD4+ T-cells were established as an interleukin-2-dependent T-cell line. When the MoL cells were exposed for a few days to conditioned medium from the T-cell line, they extended several dendritic cytoplasmic projections and became intensely positive for HLA-DR antigen, cytoplasmic S-100 beta protein, and CD1 antigen. Functionally, the conditioned medium significantly down-regulated Fc-mediated and Fc-independent phagocytic activities, and the levels of lysosomal enzymes such as lysozyme and nonspecific esterase in the MoL cells. Moreover, the conditioned medium significantly up-regulated the accessory cell function of the MoL cells as measured by the primary allogenic mixed leukocyte reaction (MLR). Furthermore, the conditioned medium significantly down-regulated the expression of CD14 antigen. Biochemical analysis indicated that the factor responsible for these changes is a protein which is distinct from known human cytokines and whose molecular weight is approximately 31 kDa. These findings suggest that IDC are closely related the monocytic lineage and that helper T-cells play an important role in constructing the microenvironment of T-lymphoid tissues which is necessary for the differentiation and maturation of IDC.

Adult↗

PubMed2006

Dynamic analysis of hepatoma spheroid formation: roles of E-cadherin and beta1-integrin.

A spheroid is an in vitro multicellular aggregate that provides a microenvironment resembling that of normal tissue in vivo. Although cell adhesion molecules such as integrins and cadherins have been implicated in participating in the process of spheroid formation, little is known about the timing of their action. In this study, we have employed an image-based quantitative method to investigate the compactness of cell aggregates during hepatoma spheroid formation in a dynamic fashion. By modulating beta1-integrin and E-cadherin activity with specific blocking antibodies, ion chelators, and RGD-sequence-containing peptides, we show that these cell adhesion molecules mediate the formation of spheroids through the establishment of complex cell-cell and cell-extracellular matrix (ECM) interactions. The dynamics of spheroid formation can be separated into three stages. In the first stage, ECM fibers act as a long-chain linker for the attachment of dispersed single-cells to form loose aggregations through the binding of integrins. This is followed by a delay period in which cell aggregates pause in compaction, presumably because of the accumulation of sufficient amounts of E-cadherins. In the third stage, strong homophilic interaction of E-cadherins is a major factor for the morphological transition from loose cell aggregates to compact spheroids. These findings thus provide comprehensive information on the molecular mechanisms and dynamics of hepatoma spheroid formation.

Cadherins↗

PubMed1992

Cytokine expression by head and neck squamous cell carcinomas.

Cytokines are known to play an important role in host defense by regulating the function, growth, and differentiation of the cells of the immune system. We hypothesize that, in the tumor microenvironment, tumor cells and resident tissue cells (e.g., fibroblasts) also produce cytokines that may regulate the local immune response to tumors. Initially, homogenates of eight head and neck squamous cell carcinomas (HNSCC) were assayed for the presence of interleukin-1 (IL-1), interleukin-4 (IL-4), interleukin-6 (IL-6), and granulocyte-macrophage colony-stimulating factor (GM-CSF) to establish the presence of these cytokines in the tumors in vivo. We detected IL-1 in all tumor homogenates and IL-4, IL-6, and GM-CSF in some homogenates. To assess the ability of HNSCC to produce these cytokines, supernatants of short-term primary cultures of HNSCC were assayed for the same cytokines. No IL-1 was detected, although baseline levels of IL-4, IL-6, and GM-CSF were present. However, the stimulation of primary tumor cultures with exogenous IL-1 induced or significantly enhanced production of IL-4 (p < 0.01), IL-6 (p < 0.001), and GM-CSF (p < 0.02). These results support our hypothesis that HNSCC secrete cytokines that may influence the response of local immune cells. Our data also suggest that IL-1 may have a central role in regulating the local immune response through the enhancement or induction of cytokine production by tumor and/or resident tissue cells.

Carcinoma, Squamous Cell↗

PubMed1989

Studies in fetal wound healing: III. Early deposition of fibronectin distinguishes fetal from adult wound healing.

Wound healing in the fetus proceeds through a series of steps that differ in the fetus and the adult. At each phase of this complex process, there is signaling between the tissue cells and the wound microenvironment, signals that are mediated by and through the extracellular matrix. We postulate that these signals occur earlier in fetal wounds, resulting in more rapid repair. To investigate this, we compared the first 24 hours of wound healing in the rabbit fetus and adult, using antibodies against key extracellular matrix macromolecular components: laminin, fibronectin, and type-specific collagens I, III, IV, and V. Fibronectin was the first matrix component to be deposited, and was visualized as early as four hours after fetal wounding and 12 hours after adult wounding. There was no evidence of new laminin or collagen deposition in either the fetal or adult wounds at any time point examined. The early deposition of fibronectin, a matrix adhesion molecule that provides a scaffolding for epithelial migration, may underlie the rapid reepithelialization observed in fetal wounds.

Animals↗

PubMed2001

The microenvironment of the tumour-host interface.

Throughout the entire process of cancer aetiology, progression and metastasis, the microenvironment of the local host tissue can be an active participant. Invasion occurs within a tumour-host microecology, where stroma and tumour cells exchange enzymes and cytokines that modify the local extracellular matrix, stimulate migration, and promote proliferation and survival. A new class of cancer therapies that targets this pathological communication interface between tumour cells and host cells is currently under development.

Animals↗

PubMed1994

Differentiation of breast cancer cells in vitro is promoted by the concurrent influence of myoepithelial cells and relaxin.

Our previous studies showed that relaxin promotes differentiation of MCF-7 breast adenocarcinoma cells. In the current investigation, we aimed to elucidate whether the effect of the hormone is potentiated when MCF-7 cells are grown together with myoepithelial cells, thus creating a microenvironment reminiscent of the organised tissue architecture of the mammary parenchyma in vivo. The findings obtained reveal that most MCF-7 cells cultured alone have an undifferentiated, blast-like phenotype, only a minority showing a more differentiated phenotype with more organelles and rudimentary intercellular junctions. When co-cultured with myoepithelial cells more MCF-7 cells acquire ultrastructural features consistent with a more differentiated phenotype, such as a rich organellular complement, apical microvilli and intercellular junctions. When relaxin was added to the co-cultures, the ultrastructural signs of differentiation could be observed in even more MCF-7 cells and became more pronounced than in the absence of the hormone, judged by the appearance of a clear-cut polarisation of cytoplasmic organelles, an almost continuous coat of apical microvilli and numerous intracellular pseudolumina.

Adenocarcinoma↗

PubMed2006

Regulation of cancer cell migration and bone metastasis by RANKL.

Bone metastases are a frequent complication of many cancers that result in severe disease burden and pain. Since the late nineteenth century, it has been thought that the microenvironment of the local host tissue actively participates in the propensity of certain cancers to metastasize to specific organs, and that bone provides an especially fertile 'soil'. In the case of breast cancers, the local chemokine milieu is now emerging as an explanation for why these tumours preferentially metastasize to certain organs. However, as the inhibition of chemokine receptors in vivo only partially blocks metastatic behaviour, other factors must exist that regulate the preferential metastasis of breast cancer cells. Here we show that the cytokine RANKL (receptor activator of NF-kappaB ligand) triggers migration of human epithelial cancer cells and melanoma cells that express the receptor RANK. RANK is expressed on cancer cell lines and breast cancer cells in patients. In a mouse model of melanoma metastasis, in vivo neutralization of RANKL by osteoprotegerin results in complete protection from paralysis and a marked reduction in tumour burden in bones but not in other organs. Our data show that local differentiation factors such as RANKL have an important role in cell migration and the tissue-specific metastatic behaviour of cancer cells.

Animals↗

PubMed1999

Role of the macrophage in erythropoiesis.

Macrophages, which are derived from precursor cells in the bone marrow, differentiate specifically under the influence of the local microenvironment. Resident macrophages in hematopoietic tissues can be distinguished from other stromal cells and monocytes by immunostaining with monoclonal antibody F4/80 and anti-Forssman glycosphingolipid antibody, respectively. Erythroid colony-forming units adhere to a resident macrophage and differentiate to erythroblasts in the presence of erythropoietin (EPO), resulting in the formation of an erythroblastic island. Resident macrophages play a supportive role in erythropoiesis, probably by preventing apoptosis of the erythroid precursors via adhesive interaction between very late activation antigen 4 and vascular cell adhesion molecule 1. Herein is proposed a model of erythropoiesis based on cooperative interaction between EPO and resident macrophages.

Animals↗

PubMed1999

Plasminogen deficiency leads to impaired remodeling after a toxic injury to the liver.

Cellular proliferation and tissue remodeling are central to the regenerative response after a toxic injury to the liver. To explore the role of plasminogen in hepatic tissue remodeling and regeneration, we used carbon tetrachloride to induce an acute liver injury in plasminogen-deficient (Plg(o)) mice and nontransgenic littermates (Plg(+)). On day 2 after CCl(4), livers of Plg(+) and Plg(o) mice had a similar diseased pale/lacy appearance, followed by restoration of normal appearance in Plg(+) livers by day 7. In contrast, Plg(o) livers remained diseased for as long as 2.5 months, with a diffuse pale/lacy appearance and persistent damage to centrilobular hepatocytes. The persistent centrilobular lesions were not a consequence of impaired proliferative response in Plg(o) mice. Notably, fibrin deposition was a prominent feature in diseased centrilobular areas in Plg(o) livers for at least 30 days after injury. Nonetheless, the genetically superimposed loss of the Aalpha fibrinogen chain (Plg(o)/Fib(o) mice) did not correct the abnormal phenotype. These data show that plasminogen deficiency impedes the clearance of necrotic tissue from a diseased hepatic microenvironment and the subsequent reconstitution of normal liver architecture in a fashion that is unrelated to circulating fibrinogen.

Afibrinogenemia↗

PubMed2002

Extensive plasma cell infiltration with crystal IgG inclusions and mutated IgV(H) gene in an osteoarthritis patient with lymphoplasmacellular synovitis. A case report.

The presence of immunoglobulin crystal inclusions in plasma cells from plasmacytomas and B-NHLs (linked to overstimulation and overproduction) has been frequently reported. Our case describes a lymphoplasmacellular synovitis in a patient with osteoarthritis (OA) showing an unusually high plasma cell infiltration and for the first time crystals in plasma cells. Using immunohistochemistry. these crystals were identified as being IgG with a balanced lambda/kappa ratio. IgV(H) gene analysis (n = 5 clones) showed that they were somatically mutated (R/S of CDR > 3): in one case, an insertion of 9 nucleotides on the CDR2 region was observed. High R/S values in the CDR indicated antigen selectivity and affinity (4/5). Since no germinal centers could be detected and the analyzed B cells showed antigen selectivity, it may be concluded that already antigenically activated B cells migrated into the synovium and locally differentiated into plasma cells, leading to the extensive infiltration observed. Rheumatoid fibroblasts were shown to support terminal B cell differentiation. Our data suggests that the ability of fibroblasts to activate B cells is not only restricted to RA, but also occurs in OA. The intense plasma cell infiltration contributed to further cartilage damage by altering the microenvironment of the nourishing synovial tissue or by the local production of pathogenic autoantibodies.

Amino Acid Sequence↗

PubMed2003

Neuroendocrine differentiation in prostatic carcinoma.

Knowledge and understanding of the pathophysiology of prostate cancer remain rudimentary. However, insight into epigenetic events and cellular interactions between cancer cells and the surrounding milieu has recently opened up a broader concept of cancer development. Throughout the entire process of prostate cancer aetiology, progression and metastasis, the microenvironment of the local host tissue is an active participant, and the selective pressure exercised on the malignant cells changes with the tumour-host setting. Thus primary cancers and metastases may respond differently to biomolecules and treatment modalities. Indeed, treatment itself changes the selective pressure, and new cellular capabilities may evolve. In prostate cancer, neuroendocrine differentiation is believed to occur in response to androgen ablation, and neuroendocrine paracrine factors have been shown to stimulate growth of androgen-independent cancer cells. Review of the accumulated knowledge in this field suggests that we need to improve our understanding of neuroendocrine cells and their regulatory products and their influence in the prostate gland. Recent research shows promise however, and no doubt new protocols will soon emerge in the treatment of prostate cancer, based on neuroendocrine hormones and their intracellular pathways.

Androgens↗

PubMedDate not supplied

Geometric control of fibroblast growth on proton beam-micromachined scaffolds.

Circular three-dimensional (3D) micropatterns with grooves and ridges of various sizes on the circumference of the structure were micromachined in polymethylmethacrylate, using proton beam micromachining. Fibroblasts were seeded in the center smooth nonpatterned surface of the circle. The circumference grooves could retard the outward spreading of cells after they became confluent in the central smooth surface. The fibroblasts eventually migrated across the grooves and ridges several days later. Wider and deeper grooves were more effective in retarding fibroblast spreading. Our results indicate that groove structures in cellular dimensions can effectively retard fibroblasts invasion. Proton beam micromachining, which has the unique advantage of being the only technique capable of manufacturing direct-write precise 3D microstructure at cellular dimensions, has great potential in generating 3D microscaffolds for studying cell behavior in a 3D microenvironment, which is important for tissue engineering.

Animals↗