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Results for “multicellular coordination”

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PubMed2026

Multicellular ecosystems: Linking cellular diversity to tissue function and disease.

Tissue function emerges from coordinated interactions among diverse cell populations, whereas disruption of these interactions can lead to dysfunction. Recent advances in single-cell and spatial genomics have not only cataloged cellular diversity but also revealed how tissues are organized as dynamic multicellular ecosystems. Moving beyond descriptive cell atlases toward functional, system-level representations represents a major frontier in tissue biology. In this review, we outline conceptual and methodological frameworks for dissecting multicellular coordination, highlight recurrent multicellular ecosystems across physiological and pathological contexts, and explore translational opportunities such as patient stratification, therapeutic reprogramming, and regenerative strategies. Viewing tissues through an ecosystem lens provides a unifying framework that links cellular diversity to emergent tissue function and informs strategies for disease intervention.

Humans↗

PubMed1991

Proteus mirabilis mutants defective in swarmer cell differentiation and multicellular behavior.

Proteus mirabilis is a dimorphic bacterium which exists in liquid cultures as a 1.5- to 2.0-microns motile swimmer cell possessing 6 to 10 peritrichous flagella. When swimmer cells are placed on a surface, they differentiate by a combination of events that ultimately produce a swarmer cell. Unlike the swimmer cell, the polyploid swarmer cell is 60 to 80 microns long and possesses hundreds to thousands of surface-induced flagella. These features, combined with multicellular behavior, allow the swarmer cells to move over a surface in a process called swarming. Transposon Tn5 was used to produce P. mirabilis mutants defective in wild-type swarming motility. Two general classes of mutants were found to be defective in swarming. The first class was composed of null mutants that were completely devoid of swarming motility. The majority of nonswarming mutations were the result of defects in the synthesis of flagella or in the ability to rotate the flagella. The remaining nonswarming mutants produced flagella but were defective in surface-induced elongation. Strains in the second general class of mutants, which made up more than 65% of all defects in swarming were motile but were defective in the control and coordination of multicellular swarming. Analysis of consolidation zones produced by such crippled mutants suggested that this pleiotropic phenotype was caused by a defect in the regulation of multicellular behavior. A possible mechanism controlling the cyclic process of differentiation and dediferentiation involved in the swarming behavior of P. mirabilis is discussed.

Cell Division↗

PubMed1997

Membrane depolarization in NRK fibroblasts by bradykinin is mediated by a calcium-dependent chloride conductance.

The effects of the phosphoinositide-mobilizing agonist bradykinin (BK) on membrane potential and intracellular calcium in monolayers of normal rat kidney (NRK) fibroblasts were investigated. BK induced a rapid transient depolarization in these cells, which was mimicked by other phosphoinositide-mobilizing factors such as prostaglandin F2alpha (PGF2alpha), lysophosphatidic acid (LPA), platelet-derived growth factor (PDGF-BB), and serum. Depolarization by BK was independent of extracellular Ca2+ or Na+. It was shown using extracellular Cl- substitutions that the depolarization was caused by an increased Cl- conductance. Depolarization was inhibited by 5-nitro-2-3-phenylpropyl(amino)benzoic acid (NPPB), niflumic acid, and flufenamic acid, inhibitors of calcium-dependent chloride channels. The depolarization provoked by BK could be mimicked by raising intracellular calcium with ionomycin or thapsigargin and could be blocked with geneticin, a blocker of phospholipase C. When intracellular calcium was buffered by loading the cells with 1,2-bis(2-aminophenoxy)ethane-NNN'N'-tetra-acetic acid (BAPTA), depolarization was prevented. We conclude that in NRK fibroblasts extracellular stimuli that increase intracellular calcium, depolarize the cells via the activation of a calcium-dependent chloride conductance. In addition to an increase in intracellular calcium, depolarization may be an important effector pathway in response to extracellular stimuli in fibroblasts. It is hypothesized that, in electrically coupled cells such as NRK fibroblasts, intercellular transmission of these depolarizations may represent a mechanism to coordinate uniform multicellular responses to Ca2+-mobilizing agonists.

Animals↗

PubMed2007

Fabrication of three-dimensional tissues.

The goal of tissue engineering is to restore or replace the lost functions of diseased or damaged organs. Ideally, engineered tissues should provide nutrient transport, mechanical stability, coordination of multicellular processes, and a cellular microenvironment that promotes phenotypic stability. To achieve this goal, many engineered tissues require both macro- (approximately cm) and micro- (approximately 100 microm) scale architectural features. In recent years, techniques from the manufacturing world have been adapted to create scaffolds for tissue engineering with defined three-dimensional architectures at physiologically relevant length scales. This chapter reviews three-dimensional fabrication techniques for tissue engineering, including: acellular scaffolds, cellular assembly, and hybrid scaffold/cell constructs.

Biocompatible Materials↗

PubMed2000

Involvement of gap junctional communication in myogenesis.

Cell-to-cell communication plays important roles in development and in tissue morphogenesis. Gap junctional intercellular communication (GJIC) has been implicated in embryonic development of various tissues and provides a pathway to exchange ions, secondary messengers, and metabolites through the intercellular gap junction channels. Although GJIC is absent in adult skeletal muscles, the formation of skeletal muscles involves a sequence of complex events including cell-cell interaction processes where myogenic cells closely adhere to each other. Much experimental evidence has shown that myogenic precursors and developing muscle fibers can directly communicate through junctional channels. This review summarizes current knowledge on the GJIC and developmental events involved in the formation of skeletal muscle fibers and describes recent progress in the investigation of the role of GJIC in myogenesis: evidence of gap junctions in somitic and myotomal tissue as well as in developing muscle fibers in situ, GJIC between perfusion myoblasts in culture, and involvement of GJIC in cytodifferentiation of skeletal muscle cells and in myoblast fusion. A model of intercellular signaling is proposed where GJIC participates to coordinate a multicellular population of interacting myogenic precursors to allow commitment to the skeletal muscle fate.

Animals↗

PubMed2000

Bacterial motility: how do pili pull?

Forceful retraction of a bacterial pilus has been directly observed for the first time. As retraction clarifies the basic mechanochemistry of single cell twitching and gliding movements, so cell-to-cell signalling by contact clarifies the coordination of multicellular gliding movements.

Bacterial Physiological Phenomena↗

PubMed1999

High cAMP in spores of Dictyostelium discoideum: association with spore dormancy and inhibition of germination.

Signalling mechanisms involving cAMP have a well-documented role in the coordination of multicellular development and differentiation leading to spore formation in the social amoeba, Dictyostelium discoideum. The involvement of cAMP in the poorly understood developmental stages of spore dormancy and germination have been investigated in this study. Dormant spores contained up to 11-fold more cAMP than nascent amoebae. The spore cAMP levels were not constant, but typically underwent a surge at 14-18 d when spores acquired the ability to germinate spontaneously. The high cAMP levels decreased only during successful spore germination, i.e. emergence of nascent amoebae. The temporal pattern of cAMP decrease was complex and unique to the method of spore activation, supporting our hypothesis that exogenously (e.g. heat) activated and autoactivated spores germinate by different mechanisms. During heat-induced activation, transcription of acg (a gene encoding adenylyl cyclase associated with germination) correlated well with spore cAMP content. Young wild-type spores, incapable of spontaneous germination, maintained a uniformly high cAMP level, and spore cAMP levels also remained high if germination was inhibited. When activated spores were deactivated by applying increased osmotic pressure, cAMP concentrations rose and ultimately levelled off at the high levels typical of dormant spores. The correlation between high cAMP and failure to germinate was also evident when autoactivation was inhibited by the cAMP analogue, 8-bromo-cAMP. Also, spores from a strain (HTY217) with unrestrained protein kinase A activity were incapable of spontaneous germination. Overall, our experiments provide evidence for continued cAMP signalling in spores up to 18 d after sporulation and for linkages between elevated cAMP, spore deactivation and inhibition of spontaneous germination.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed2003

Identification of the C-signal, a contact-dependent morphogen coordinating multiple developmental responses in Myxococcus xanthus.

The regulated accumulation of the contact-dependent extracellular C-signal morphogen in the bacterium Myxococcus xanthus ensures the temporal and spatial coordination of multicellular morphogenesis and cellular differentiation during fruiting body formation. Synthesis of the C-signal depends on the csgA gene. The CsgA protein exists in two forms, the full-length 25-kD protein (p25), which is homologous to short-chain alcohol dehydrogenases, and a 17-kD protein (p17). The molecular nature of the C-signal has remained elusive. Here we show that p25 and p17 are associated with the outer membrane and that p17 copurifies with C-signal activity from M. xanthus cells. p17 corresponds to the C-terminal part of p25. A recombinant p17 protein, which lacks the N-terminal coenzyme binding pocket and which fails to bind NAD+ in vitro, has C-signal activity. These data provide evidence that p17 is the active species in C-signaling and that p17 does not act as a short-chain alcohol dehydrogenase to generate the C-signal. We further provide evidence that p17 is synthesized by N-terminal proteolytic processing of p25 by a serine protease. Compared to other bacterial signaling molecules, p17 is unusual with respect to size and cell-surface association. In these regards, C-signal is functionally analogous to eukaryotic signaling proteins.

Amino Acid Sequence↗

PubMed1992

Control of cell density and pattern by intercellular signaling in Myxococcus development.

Myxococcus xanthus cells feed, move, and develop cooperatively. Genetic, biochemical, and cell mosaic studies demonstrate that cells coordinate their multicellular behavior by transmission of intercellular signals. Starvation for amino acids at sufficiently high density on a solid surface initiates a series of events culminating in the formation of a multicellular structure called a fruiting body filled with dormant, environmentally resistant spores. This review discusses how myxobacteria use extracellular signals to sequentially check the density and arrangement of cells at different stages during development. For at least one early and one late developmental signal, cell density determines the efficiency of intercellular signaling. In turn, proper signaling insures that the appropriate cell density exists, thus controlling the progress of multicellular development in M. xanthus.

Colony Count, Microbial↗

PubMed1997

Synchronized Ca2+ signaling by intercellular propagation of Ca2+ action potentials in NRK fibroblasts.

The intercellular propagation of Ca2+ waves by diffusion of inositol trisphosphate has been shown to be a general mechanism by which nonexcitable cells communicate. Here, we show that monolayers of normal rat kidney (NRK) fibroblasts behave like a typical excitable tissue. In confluent monolayers of these cells, Ca2+ action potentials can be generated by local depolarization of the monolayer on treatment with either bradykinin or an elevation of the extracellular K+ concentration. These electronically propagating action potentials travel intercellularly over long distances in an all-or-none fashion at a speed of approximately 6.1 mm/s and can be blocked by L-type Ca2+ channel blockers. The action potentials are generated by depolarizations beyond the threshold value for L-type Ca2+ channels of about -15 mV. The result of these locally induced, propagating Ca2+ action potentials is an almost synchronous, transient increase in the intracellular Ca2+ concentration in large numbers of cells. These data show that electrically coupled fibroblasts can form an excitable syncytium, and they elucidate a novel mechanism of intercellular Ca2+ signaling in these cells that may coordinate synchronized multicellular responses to local stimuli.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1998

The characterization of two Dictyostelium discoideum genes encoding ribosomal proteins with sequence similarity to rat L27a and L37a.

Two Dictyostelium discoideum ribosomal protein genes, denoted DdL27a and DdL37a, were isolated and sequenced. The DdL27a gene contained an open reading frame of 148 amino acids coding for a putative 16,407 Da protein, which was similar to rat L27a (82.6% similarity) and to ribosomal proteins from other species. The gene contained a 311-bp intron downstream from the ATG initiation codon with an A+T content of 75%. The DdL37a gene encoded a 9,999 Da protein consisting of 91 amino acids, which had high sequence similarity to rat, human, and chicken ribosomal protein L37a, and was interrupted by two introns of 254 bp and 75 bp in length. The DdL37a protein contained a typical zinc finger motif (Cys-X2-Cys-X14-Cys-X2-Cys), which may be involved in the interaction of proteins with nucleic acids. Genomic DNA blot analysis indicated that the DdL27a and DdL37a genes are present in single copies in the Dictyostelium haploid genome. The DdL27a and DdL37a mRNA were expressed maximally in growing amoebae, and their levels decreased during multicellular development, coordinately with the observed decrease in ribosome accumulation during later development.

Amino Acid Sequence↗

PubMed1993

[Intercellular communication and signal transduction mechanisms].

Cells in multicellular organisms coordinate their functions by signalling molecules serving as means of communication. Specific receptors enable transduction of chemical information from extracellular environment into a cell. Inside the cell the signal is multiplied and transduced further by intracellular signalling molecules and enzymatic cascades. Phosphorylation of proteins on tyrosine, serine or threonine residues, guanosine triphosphate binding by special G proteins and regulation of DNA transcription seem to be the most important biochemical mechanisms of signal transduction. Products of cellular protooncogenes are involved in all levels of signal transduction, the detailed knowledge of signal pathways is therefore important for our understanding of pathophysiology of malignant disease and strategies for the therapeutic use of growth factors in oncology and haematology.

Cell Communication↗

PubMed1999

A novel membrane protein influencing cell shape and multicellular swarming of Proteus mirabilis.

Swarming in Proteus mirabilis is characterized by the coordinated surface migration of multicellular rafts of highly elongated, hyperflagellated swarm cells. We describe a transposon mutant, MNS185, that was unable to swarm even though vegetative cells retained normal motility and the ability to differentiate into swarm cells. However, these elongated cells were irregularly curved and had variable diameters, suggesting that the migration defect results from the inability of these deformed swarm cells to align into multicellular rafts. The transposon was inserted at codon 196 of a 228-codon gene that lacks recognizable homologs. Multiple copies of the wild-type gene, called ccmA, for curved cell morphology, restored swarming to the mutant. The 25-kDa CcmA protein is predicted to span the inner membrane twice, with its C-terminal major domain being present in the cytoplasm. Membrane localization was confirmed both by immunoblotting and by electron microscopy of immunogold-labelled sections. Two forms of CcmA were identified for wild-type P. mirabilis; they were full-length integral membrane CcmA1 and N-terminally truncated peripheral membrane CcmA2, both present at approximately 20-fold higher concentrations in swarm cells. Differentiated MNS185 mutant cells contained wild-type levels of the C-terminally truncated versions of both proteins. Elongated cells of a ccmA null mutant were less misshapen than those of MNS185 and were able to swarm, albeit more slowly than wild-type cells. The truncated CcmA proteins may therefore interfere with normal morphogenesis, while the wild-type proteins, which are not essential for swarming, may enhance migration by maintaining the linearity of highly elongated cells. Consistent with this view, overexpression of the ccmA gene caused cells of both Escherichia coli and P. mirabilis to become enlarged and ellipsoidal.

Amino Acid Sequence↗

PubMed1998

Induction of optical density waves and chemotactic cell movement in Dictyostelium discoideum by microinjection of cAMP pulses.

The development of most multicellular organisms involves coordinated cell movement. The early aggregation of Dictyostelium cells has been shown to be mediated by chemotactic movement to propagating waves of cAMP. We have proposed that propagating waves of a chemoattractant, most likely cAMP, also control the movement of cells in mounds and slugs. We have now used periodic pressure injection of pulses of cAMP in the extracellular space of aggregation streams, mounds, and slugs to investigate whether these signals can be relayed and control cell movement, using quantitative digital time-lapse microscopy. Our major findings are (1) short (0.1 s) pulses of cAMP (10(7) molecules) were able to elicit optical density (OD) waves in fields of aggregating amoebae. They propagate from the micropipet outward and interact with endogenous OD waves. (2) Periodic injection of cAMP pulses into aggregation streams blocked the pulses coming from the center and led to the rapid accumulation of cells downstream of the pipet around the pipet. (3) Injection of pulses of cAMP into mounds elicited OD waves, which propagated from the pipet outward and interacted with the endogenous waves, indicating that the same propagator carries them. (4) Periodic microinjection of cAMP in the prespore zone of slugs led to accumulation of anterior-like cells around the micropipet followed by tip formation. Furthermore, the cAMP signal could control the spacing of the endogenous sorting pattern. These results strongly support the hypothesis that the optical density waves observed during early development up to the mound stage represent propagating cAMP waves. They suggest furthermore that cAMP is the morphogen that controls cell movements in slugs.

Animals↗

PubMed2007

Silence is golden: combining RNAi and live cell imaging to study cell cycle regulatory genes during Caenorhabditis elegans development.

Much of the pioneering work on the genetics of cell cycle regulation was accomplished using budding and fission yeast. The relative simplicity of these single-celled organisms allowed investigators to readily identify and assign roles to individual genes. While the molecular mechanisms worked out in yeast are more or less identical to those operating in higher organisms, additional layers of control must exist in multicellular organisms to coordinate the timing of developmental events occurring in different cells and tissues. Here we discuss experimental approaches for studying cell cycle processes in the nematode Caenorhabditis elegans.

Animals↗

PubMed2001

Regulation of gap junctional communication by a pro-inflammatory cytokine in cystic fibrosis transmembrane conductance regulator-expressing but not cystic fibrosis airway cells.

Airway inflammation is orchestrated by cell-cell interactions involving soluble mediators and cell adhesion molecules. Alterations in the coordination of the multicellular process of inflammation may play a major role in the chronic lung disease state of cystic fibrosis (CF). The aim of this study was to determine whether direct cell-cell interactions via gap junctional communication is affected during the inflammatory response of the airway epithelium. We have examined the strength of intercellular communication and the activation of nuclear factor-kappaB (NF-kappaB) in normal (non-CF) and CF human airway cell lines stimulated with tumor necrosis factor-alpha (TNF-alpha). TNF-alpha induced maximal translocation of NF-kappaB into the nucleus of non-CF as well as CF airway cells within 20 minutes. In non-CF cells, TNF-alpha progressively decreased the extent of intercellular communication. In contrast, gap junctional communication between CF cells exposed to TNF-alpha remained unaltered. CF results from mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Interestingly, transfer of wild-type CFTR into CF cells by adenovirus-mediated infection was associated with the recovery of TNF-alpha-induced uncoupling. These results suggest that expression of functional CFTR is necessary for regulation of gap junctional communication by TNF-alpha. Gap junction channels close during the inflammatory response, therefore limiting the intercellular diffusion of signaling molecules, and thereby the recruitment of neighboring cells. Defects in this mechanism may contribute to the excessive inflammatory response of CF airway epithelium.

Bronchi↗

PubMed1997

Growth factor-dependent phosphoinositide signalling.

A wide variety of messages, in the form of diffusible growth factors, hormones and cytokines, are carried throughout multicellular organisms to coordinate important physiological properties of target cells, such as proliferation, differentiation, migration, apoptosis and metabolism. Most messengers bind to cognate receptors on target cells, which initiate a characteristic cascade of reactions within the cell, ultimately leading to the desired response. The cellular response is defined by the combination of signalling components whose individual activity depends upon the number and type of surface receptors. Consequently the responses of different cell types to one or more stimuli can be quite disparate. A molecular understanding of the signalling pathways employed by each type of receptor therefore underlies the ability to rationalize many cellular functions and to correct disfunctions. As a well studied example of the primary signalling events that take place on the cytoplasmic leaflet of the plasma membrane following receptor activation, we will discuss how the widely expressed receptor for epidermal growth factor (EGF) causes the phosphorylation and hydrolysis of a signalling precursor, the membrane lipid phosphatidylinositol. This paradigm will be used to illustrate certain general principles of signalling, including formation of multienzyme complexes, compartmentation of second messengers and intermediates, and cross-talk between different signalling pathways.

1-Phosphatidylinositol 4-Kinase↗

PubMed2002

Networks and crosstalk: integrin signalling spreads.

Multicellular organisms must coordinate signals from adhesion receptors with those from other signalling receptors (for example, growth factor receptors). Here, we briefly review paradigms of integrin-adhesion-receptor signalling. We discuss how adhesive signalling is coordinately regulated through intersecting networks. We also examine some examples of how some forms of integrin crosstalk may lead to unforeseen and potentially deleterious responses.

Animals↗