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PubMed2006

Magnetic optimization in a multicellular magnetotactic organism.

Unicellular magnetotactic prokaryotes, which typically carry a natural remanent magnetic moment equal to the saturation magnetic moment, are the prime example of magnetically optimized organisms. We here report magnetic measurements on a multicellular magnetotactic prokaryote (MMP) consisting of 17 undifferentiated cells (mean from 148 MMPs) with chains of ferrimagnetic particles in each cell. To test if the chain polarities of each cell contribute coherently to the total magnetic moment of the MMP, we used a highly sensitive magnetization measurement technique (1 fAm(2)) that enabled us to determine the degree of magnetic optimization (DMO) of individual MMPs in vivo. We obtained DMO values consistently above 80%. Numerical modeling shows that the probability of reaching a DMO > 80% would be as low as 0.017 for 17 randomly oriented magnetic dipoles. We simulated different scenarios to test whether high DMOs are attainable by aggregation or self-organization of individual magnetic cells. None of the scenarios investigated is likely to yield consistently high DMOs in each generation of MMPs. The observed high DMO values require strong Darwinian selection and a sophisticated reproduction mechanism. We suggest a multicellular life cycle as the most plausible scenario for transmitting the high DMO from one generation to the next.

Cell Aggregation↗
PubMed2006

The cloning and characterization of the histone acetyltransferase human homolog Dmel\TIP60 in Drosophila melanogaster: Dmel\TIP60 is essential for multicellular development.

Chromatin packaging directly influences gene programming as it permits only certain portions of the genome to be activated in any given developmental stage, cell, and tissue type. Histone acetyltransferases (HATs) are a key class of chromatin regulatory proteins that mediate such developmental chromatin control; however, their specific roles during multicellular development remain unclear. Here, we report the first isolation and developmental characterization of a Drosophila HAT gene (Dmel\TIP60) that is the homolog of the human HAT gene TIP60. We show that Dmel\TIP60 is differentially expressed during Drosophila development, with transcript levels significantly peaking during embryogenesis. We further demonstrate that reducing endogenous Dmel\TIP60 expression in Drosophila embryonic cells by RNAi results in cellular defects and lethality. Finally, using a GAL4-targeted RNAi system in Drosophila, we show that ubiquitous or mesoderm/muscle-specific reduction of Dmel\TIP60 expression results in lethality during fly development. Our results suggest a mechanism for HAT regulation involving developmental control of HAT expression profiles and show that Dmel\TIP60 is essential for multicellular development. Significantly, our inducible and targeted HAT knockdown system in Drosophila now provides a powerful tool for effectively studying the roles of TIP60 in specific tissues and cell types during development.

Amino Acid Sequence↗
PubMed1997

The effects of growth factors on multicellular spheroids formed by chick embryonic retinal cells.

Retinal cells from chick embryos aged 7.5 days of gestation were cultured for two months in a non-adherent suspension culture dish to study the effects of growth factors and co-culture with retinal pigment epithelial cells on their differentiation. Dissociated retinal cells became cellular aggregates (multicellular spheroids) within a day, and rosettes were formed in the spheroids after 2 days. Ultrastructurally, neurons of the rosettes developed connecting cilia, ellipsoids (accumulation of mitochondria), and external limiting membrane, indicative of their differentiation into photoreceptor cells. Epidermal growth factor enhanced the expression of rhodopsin by rosette-forming neurons, while basic fibroblast growth factor induced the growth of Mueller cells at 4 weeks, and their transdifferentiation into lens-epithelial-like cells at 8 weeks. Co-culture of retinal cells with retinal pigment epithelial cells enhanced the formation of rosettes in spheroids. Multicellular spheroids formed in a dish for suspension culture would provide a convenient in vitro system to examine differentiation and transdifferentiation of the retina.

Animals↗
PubMed1998

[Assay system for tumor control effect using encapsulated multicellular spheroid models].

Most advanced head and neck cancers are inoperable, hence they are treated by either radiotherapy or combined chemoradiotherapy. More effective methods of combined chemoradiotherapy are certainly required for improving the curability of these cancers. Numerous factors involved in modifying the effectiveness have to be quantitatively analyzed for improvement; this has been a limiting factor preventing therapeutic progress. The purpose of the present study was to establish an experimental technique for assessing the in vivo effect of radiotherapy or chemoradiotherapy on multicellular tumor spheroids encapsulated in a semitransparent microcapsule. Mouse squamous carcinoma cells suspended in sodium alginate solution were transferred to a syringe connected to an air jet apparatus. Droplets containing cells were dropped into a calcium chloride solution, which caused them to gel, and then treated with poly L-lysine solution. The encapsulated cells were cultured in vitro for three weeks to form multicellular spheroids with central necrosis. The spheroids were either X-irradiated in vitro or in vivo by grafting in a nude mouse. The dose-cell survival curve in vivo was biphasic with a radioresistant component which was not observed in vitro. This method was considered to be applicable to human tumor cells and useful for determining the effectiveness of therapeutic agent as human solid tumor models in vivo.

Animals↗
PubMed1999

Adhesion-dependent multicellular drug resistance.

Herein we review studies demonstrating resistance manifested at the multicellular level, a phenomenon referred to as intrinsic or acquired multicellular resistance (MR). In addition, due to the fact that such resistance can be recapitulated in vitro only when cells are adhered to one another in a three-dimensional culture context, we examine the roles of cell adhesion molecules and how they may contribute directly or indirectly to MR. Finally, we suggest an experimental approach to circumvent MR in the treatment of advanced, aggressive ascites tumors.

Animals↗
PubMedDate not supplied

Differential endothelial CAM-expression after stimulation with supernatants of LPS- and cytokine-stimulated HT-29 and ST-ML-12 tumor cells growing as monolayer cultures and multicellular spheroids.

The mechanisms of tumor metastasis in vitro have been principally investigated using monolayer culture systems. In vivo, however, multicellular clusters of tumor cells rather than individual cells appear to penetrate the microvasculature. Thus, the multicellular tumor spheroid model represents a more suitable tool to study tumor cell-endothelial interactions. Our interest has centered on the role of inflammation on tumor intra- and extravasation. The expression of three endothelial cell adhesion molecules (CAM), ICAM-1, VCAM-1 and E-selectin, on HUVEC after incubation with supernatants of previously LPS-, TNF-alpha- or IL-1 beta-stimulated HT-29 (colon adenocarcinoma) and ST-ML-12 (melanoma) tumor cells growing as monolayers and spheroids, was compared using cell enzyme immunoassay. The results indicated that important differences in the expression of CAM between monolayers and spheroids exist depending on the tumor cell line. The possible significance of LPS for colon carcinomas was underlined by the spheroid-model results. With respect to the influence of intestinal bacteria on the behaviour of colon carcinomas, the spheroid model could be a useful in vitro system for a more realistic simulation of in vivo conditions.

Cell Adhesion Molecules↗
PubMed2003

Boundary formation by notch signaling in Drosophila multicellular systems: experimental observations and gene network modeling by Genomic Object Net.

The Delta-Notch signaling system plays an essential role in various morphogenetic systems of multicellular animal development. Here we analyzed the mechanism of Notch-dependent boundary formation in the Drosophila large intestine, by experimental manipulation of Delta expression and computational modeling and simulation by Genomic Object Net. Boundary formation representing the situation in normal large intestine was shown by the simulation. By manipulating Delta expression in the large intestine, a few types of disorder in boundary cell differentiation were observed, and similar abnormal patterns were generated by the simulation. Simulation results suggest that parameter values representing the strength of cell-autonomous suppression of Notch signaling by Delta are essential for generating two different modes of patterning: lateral inhibition and boundary formation, which could explain how a common gene regulatory network results in two different patterning modes in vivo. Genomic Object Net proved to be a useful and flexible biosimulation system that is suitable for analyzing complex biological phenomena such as patternings of multicellular systems as well as intracellular changes in cell states including metabolic activities, gene regulation, and enzyme reactions.

Animals↗
PubMedDate not supplied

Antitumour effects of a bispecific trivalent antibody in multicellular tumour spheroids.

BACKGROUND: New adjuvant immunological therapies that selectively redirect effector cells towards tumour cells are currently under development. These strategies include the use of bispecific antibodies as promising tools for the elimination of disseminated tumour cells and micrometastases. At present, bispecific molecules have demonstrated their antitumour potential in investigations in vitro using monolayer cell cultures. However, their effectiveness in vivo is less clear and expressive in vitro tumour models are in high demand. MATERIALS AND METHODS: Three-dimensional multicellular tumour spheroids (MTS) are of intermediate complexity between monolayer cell cultures and solid tumours in patients and therefore represent a particularly promising in vitro system. RESULTS: We show, here, the antitumour potential of a bispecific antibody, BiUII, in three-dimensional multicellular tumour spheroids and furthermore demonstrate that BiUII triggers peripheral blood mononuclear cells to invade MTSs and elicit the production of TNFalpha, resulting in the efficient destruction of tumour cells. CONCLUSION: These results demonstrate that bispecific antibodies are capable of activating immune effector cells, resulting in the elimination of three-dimensional structures of tumour cells. The therapeutic potential of these antibodies in the clinical setting merits further investigations.

Antibodies, Bispecific↗
PubMed1991

Application of (methyl-11C)-methionine in the multicellular spheroid system.

Human glioma (U-343 MGa) and human colon carcinoma (HT-29) cell lines were cultured as multicellular spheroids, and the accumulations of the L- and D-enantiomers of 11C-methionine were investigated. The accumulation of radioactivity in the spheroids was expressed as relative counts, by dividing the radioactivity measured in the spheroid with the radioactivity of the same volume of the incubation medium. The experiments were verified using 14C-labeled L- and D-methionine. The influence of spheroid volume, specific activity, incubation time, washing time, and the environmental temperatures were investigated. The spheroid model was used to determine the effect of the lipoxygenase inhibitors BW A4C and AA-861, the ether-phospholipid type PAF-antagonist CV-6209 and the protein synthesis inhibitor cycloheximide on methionine uptake. The results showed that 11C-L-methionine can be applied in the study of drug effects on multicellular tumor cell aggregates.

Benzeneacetamides↗
PubMed1990

Bacterial macrofibres: the morphogenesis of complex multicellular bacterial forms.

Bacterial macrofibres are highly ordered multicellular, helically twisted structures that provide a unique opportunity for studying fundamental growth processes and morphogenesis in a procaryotic model. The complex fibres arise, starting either from a single spore or a vegetative cell by the deformation of individual cell shape from cylindrical to helical and the folding and plying of chains of cells into multicellular twisted structures. The dynamics of fibre morphogenesis can be traced to hierarchical interactions beginning with the assembly of cell-wall polymers. Both genetic and biomechanical factors govern the formation and heritability of macrofibre twist states, which can range over the entire spectrum from maximum left- to maximum right-handedness. Forces that arise during growth influence individual cells and their interactions with other cells. Morphogenesis results from the manner in which the cell-wall materials respond to these and other forces. Significant parameters governing response to force are cell wall geometry, visco-elasticity and anisotrophy.

Bacillus subtilis↗
PubMedDate not supplied

Multicellular tumor spheroids in serum-free culture.

The serum-free culture of multicellular tumor spheroids from two rat (BT4c, BT5c) and two human (GaMg, D-54Mg) glioma cell lines is described. The spheroids were propagated in two different chemically defined media, showing differences in growth requirements between the human and rat cell lines. The spheroids from all the cell lines showed reduced growth rate as compared to spheroids maintained in serum supplemented culture. A change in spheroid morphology was observed for the D-54Mg cell line, indicated by a reduced occurrence of microvilli, increased pyknosis and cellular granularity. The other spheroids maintained their morphology in serum-free culture. For the D-54 Mg spheroids, flow cytometric DNA measurements showed that the serum-free growth conditions caused a drop in the DNA S-phase (6.4% vs. 12.3% in serum supplemented cultures). The cell cycle distribution was unchanged for the other cell lines tested. The present study provides the basis for using multicellular tumor spheroids in biological studies which are dependent on a detailed control with chemical environment.

Animals↗
PubMed1988

Hematon: a multicellular functional unit in primary hematopoiesis.

Bone marrow aspirates from healthy donors contain a fraction of low density multicellular spheroids, 100-500 microns in diameter. They are organized in a three-dimensional network consisting of central preadipocytes/adipocytes, mesenchymal and reticular cells, and resident macrophages that are closely associated with myeloid, erythroid and megakaryocyte progenitor cells and with their progenies. These spheroids are 2- to 5- fold more abundant in progenitor cells compared with the whole bone marrow as estimated by monoclonal antibody markers My 10 and T 9, by analysis of granulocyte--macrophage colony forming cells (GM-CFC) and by cytological techniques. They produce terminally differentiated cells in organotypic microcultures. We suggest that a multicellular spheroid may represent the fundamental unit of primary hematopoiesis; we therefore name it hematon. Here we show that the presence of hematons in bone marrow aspirates correlated positively with homeostatic blood cell production: they were present in normal bone marrow (BM) (19/25), and absent in myelodysplasic syndromes (MDPS) (8/21), in acute nonlymphocytic leukemias (ANLL) (3/22) and in chronic myeloid leukemia (CML) (2/28). The hematons were recovered under hematological remission in MDPS and in ANLL, suggesting that they may be dispersed reversibly in certain disease conditions. The hematons represent a unifying model around which the variability in some bone marrow cell functions can be explored.

Bone Marrow↗
PubMed1987

1H NMR techniques in studies of transport of paramagnetic ions in multicellular systems.

Two different pulse sequences used in 1H NMR spectroscopy termed free induction decay amplitude recovery (FIDAR) and spin-echo recovery (SER) were applied to studies of transport of paramagnetic ions in multicellular systems. The molar relaxivity of several paramagnetic species (Fe3+, Co2+, Ni2+, Cu2+, Mn2+, MnEDTA2-, dextran-magnetite) in water solutions was measured at 32 MHz resonance frequency. Ionic transport was studied using Mn2+ and MnEDTA2- as models for cations and anions, respectively, and plant root tissue as a model of a multicellular system.

Algorithms↗
PubMed1987

Theoretical prerequisites for an experimental corroboration of the existence of a specialized cellular system in control of multicellular organism tissue proliferation.

A theoretical analysis of cell proliferation as a selflimiting process designed to maintain the integrity of an entire multicellular organism and based on the principles of a "hypercycle" suggests the need for the existence, starting at a certain level of multicellular organization, of a specialized system in control of tissue proliferation, a system represented by a body of cells capable of both stimulating and inhibiting the proliferation of a variety of cell types. An analysis of experimental data in different fields of the biological science points to certain T-cell populations as probable candidate for the role of cellular regulators of tissue proliferation. Using as an example the induction of murine liver regeneration by the administration of CCL4, the author demonstrates the dynamics of the formation of cells stimulating and inhibiting regeneration, which conforms well to theoretical considerations.

Animals↗
PubMed1984

A multistage model for the action of cytotoxic T lymphocytes in multicellular conjugates.

We propose a multistage stochastic model to explain data on the kinetics of target cell lysis by cytotoxic T lymphocytes in multicellular conjugates. A novel feature of our model is that we explicitly consider both the lethal hitting stage and the target cell disintegration stage of the cytolytic process. Further, we allow for the possibility that target cell disintegration is itself a complex process composed of many events. The comparison of our model with the data of other investigators suggests that cytotoxic T cells deliver lethal hits at random to undamaged target cells. Having received a lethal hit, the target cell disintegrates over a variable length of time. The disintegration times of target cells from different conjugates appear to be randomly distributed and to be consistent with a model in which disintegration occurs by at least two major, sequential, rate-limiting events. For conjugates containing one lymphocyte and multiple target cells, the mean rate at which a lethally hit target cell disintegrates is found to be independent of the total number of target cells in the conjugate. Our model predicts that in such multicellular conjugates, individual target cells lyse one by one, on average at approximately 30-min intervals, thus agreeing closely with previously reported experimental observations.

Cell Communication↗
PubMedDate not supplied

[Use of multicellular spheroids in studies based on the NSD (nominal standard dose) concept].

The authors discuss the possibility of application of multicellular spheroids as a model system in studies based on NSD conception. The death rate of spheroids from cells of Chinese hamster V79-4 was shown to depend upon cumulative dose of gamma- and neutron (0.7 MeV)-radiation (the number of fractions was 1, 5 and 10). With fractionated irradiation, the reoxygenation effect was observed. A good coincidence was obtained between the dependence of the cumulative dose upon the number of fractions for multicellular spheroids and clinical data.

Animals↗
PubMed1980

The multicellular tumor spheroid model. II. Characterization of the primary allograft response in unsensitized mice.

The multicellular spheroid model previously has been used to characterize secondary allograft responses in sensitized mice. In this study multicellular spheroids of EMT6 mammary sarcoma were implanted into unsensitized allogeneic mice to assess sensitization, graft infiltration, and functional activities of host cells in a primary allograft response. During the first 5 days after implantation, the spheroids continued to grow similar to controls maintained in vitro. After 6 days the spheroids decreased in size, and recovery of clonogenic tumor cells fell markedly. Cytotoxic effector cells active in an in vitro 51Cr release assay were recoverable from the spheroids beginning at day 4 and reached a maximum at day 7. Lymphocytes and macrophages were present in the largest numbers at days 7 to 8. The predominant cytotoxic cell appears to be a T lymphocyte.

Animals↗
PubMed1981

Single or multicellular origin of human T lymphocyte colonies in vitro: modification by 12-o-tetradecanoylphorbol 13-acetate (TPA).

The assumption that human T lymphocyte colonies have a unicellular origin has been directly tested with peripheral blood mononuclear cells from 2 women heterozygous for the common X-linked glucose-6-phosphate dehydrogenase (G-6-PD) gene (GdB) and the variant GdA. T cells were cultured in semisolid medium in the presence of phytohemagglutinin (PHA) and T lymphocyte growth factor with or without preincubation in suspension culture with PHA (2-stage and 1-stage assays, respectively). The enzyme type of individual T cell colonies was then determined electrophoretically at the lowest colony density with adequate growth (usually less than 100 colonies/dish). In the 2-stage system, 90 of 97 tested colonies had equal amounts of A and B enzyme activities suggesting multicellular origin of the colonies. Similarly, in the single-stage system, 21 of 31 colonies had both A and B enzymes. Increasing the density of the soft agar did not influence the frequency of A/B colonies. However, when 12-O-tetradecanoylphorbol 13-acetate (TPA), a promoter of T cell colony growth shown in other systems to inhibit metabolic cooperation, was added, a striking decrease in frequency of colonies with both G-6-PD types was found. In the 2-stage culture, 0 of 9 colonies had a double-enzyme type and in the single-stage system, the frequency of A/B colonies declined to 9 of 34 (p less than 0.025). The data suggest that despite the apparent multicellular origin of T cell colonies in cultures with TPA, most colonies do originate from single cells when cultured with TPA at low colony densities. Stimulation of cell growth or inhibition of metabolic cooperation between cells by TPA are possible explanations for these differences.

Cells, Cultured↗