Metabolic iteration,evolution and cognition in cellular proliferation

Summary A model for cellular proliferation is described according to which proliferation ensues when metabolism evolves towards commitment to DNA synthesis, and inhibition of proliferation occurs when enzymic interactions are iterated within a few metabolic pathways, another limiting factor being the supply of metabolites. The model successfully describes cellular growth and division as a cognitive process based on interaction within enzymic elements and the genome, and affords an explanation in these terms of some empirical phenomena which have previously been understood only as isolated observations.     

Modeling melanoblast development

Melanoblasts are a particular type of cell that displays extensive cellular proliferation during development to contribute to the skin. There are only a few melanoblast founders, initially located just dorsal to the neural tube, and they sequentially colonize the dermis, epidermis, and hair follicles. In each compartment, melanoblasts are exposed to a wide variety of developmental cues that regulate their expansion. The colonization of the dermis and epidermis by melanoblasts involves substantial proliferation to generate thousands of cells or more from a few founders within a week of development. This review addresses the cellular and molecular events occurring during melanoblast development. We focus on intrinsic and extrinsic factors that control melanoblast proliferation. We also present a robust mathematical model for estimating the doubling-time of dermal and epidermal melanoblasts for all coat color phenotypes from black to white.     

Une note concernant la centrifugation fractionnée de foie de rat

Summary Significant differences were observed in enzymic composition of L and P fractions between fasting and fed animals. The L fraction contains a smaller percentage and the P fraction a higher percentage of the enzymic activity of the homogenate when the rat is fed, which can be explained by the sedimentation in the L fraction of a high proportion of the glycogen accumulated in the liver of fed animals. The presence of this component changes the organization of the centrifugation pellet so that, during the decantation of the L fraction, subcellular structures sedimenting in this fraction are sucked off and recuperated in the next centrifugation pellet, i.e. in the microsomal P fraction.     

Cortisone sensitive T-cells in Peyers' patches.

Pretreatment of donor lymphoid cells with cortisone has been shown to depress the T-cell subpopulation responsible for cellular proliferation in the GVH reaction. A quantitative assay as well as the histological criteria of the GVH reaction have been used in this study to demonstrate the presence of cortisone-sensitive T-cells within the Peyer's patches as well as in the spleen and mesenteric lymph nodes in the rat.     

A unifying model of the cell proliferation emphasizing plasma membrane fluxes

The regulation of cellular growth and proliferation is perhaps the most investigated and elusive problem in cell biology and seems to be possible to solve from almost any angle of study chosen. Among the non-systemic factors that have been discussed are genetic damage, genomic control, regulation by stimulatory and inhibitory peptide factors such as EGF, chalones, and fibronectin, protein kinase activation with tyrosine phosphorylation, adenylylcyclase and cAMP, cGMP, membrane perturbations and specifically in tumours the failure of the Pasteur effect in control of glycolysis, excessive membrane ATPase activity, and excessive hydrolytic and proteolytic activities at the cell surface. This article focuses on the central role of fluxes within the plasma membrane and re-examines the possibility that changes of flux of metabolites, ions, and reducing equivalents may be the common denominator regulating cellular proliferation.     

Sphingolipids in mammalian cell signalling

Sphingolipids and their metabolites, ceramide, sphingosine and sphingosine-1-phosphate, are involved in a variety of cellular processes including differentiation, cellular senescence, apoptosis and proliferation. Ceramide is the main second messenger, and is produced by sphingomyelinase-induced hydrolysis of sphingomyelin and by de novo synthesis. Many stimuli, e.g. growth factors, cytokines, G protein-coupled receptor agonists and stress (UV irradiation) increase cellular ceramide levels. Sphingomyelin in the plasma membrane is located primarily in the outer (extracellular) leaflet of the bilayer, whilst sphingomyelinases are found at the inner (cytosolic) face and within lysosomes/endosomes. Such cellular compartmentalisation restricts the site of ceramide production and subsequent interaction with target proteins. Glycosphingolipids and sphingomyelin together with cholesterol are major components of specialised membrane microdomains known as lipid rafts, which are involved in receptor aggregation and immune responses. Many signalling molecules, for example Src family tyrosine kinases and glycosylinositolphosphate-anchored proteins, are associated with rafts, and disruption of these domains affects cellular responses such as apoptosis. Sphingosine and sphingosine-1-phosphate derived from ceramide are also signalling molecules. In particular, sphingosine-1-phosphate is involved in proliferation, differentiation and apoptosis. Sphingosine-1-phosphate can act both extracellularly through endothelial-differentiating gene (EDG) family G protein-coupled receptors and intracellularly through direct interactions with target proteins. The importance of sphingolipid signalling in cardiovascular development has been reinforced by recent reports implicating EDG receptors in the regulation of embryonic cardiac and vascular morphogenesis. Received 16 May 2001; received after revision 29 June 2001; accepted 3 July 2001     

A unifying model of the cell proliferation emphasizing plasma membrane fluxes

Summary The regulation of cellular growth and proliferation is perhaps the most investigated and elusive problem in cell biology and seems to be possible to solve from almost any angle of study chosen. Among the non-systemic factors that have been discussed are genetic damage, genomic control, regulation by stimulatory and inhibitory peptide factors such as EGF, chalones, and fibronectin, protein kinase activition with tyrosine phosphorylation, adenylylcyclase and cAMP, cGMP, membrane perturbations and specifically in tumours the failure of the Pasteur effect in control of glycolysis, excessive membrane ATPase activity, and excessive hydrolytic and proteolytic activities at the cell surface. This article focusses on the central role of fluxes within the plasma membrane and re-examines the possibility that changes of flux of metabolites, ions, and reducing equivalents may be the common denominator regulating cellular proliferation.     

Olfactory ensheathing cells promote neurite sprouting of injured axons in vitro by direct cellular contact and secretion of soluble factors

Olfactory ensheathing cells (OECs) represent an exciting possibility for promoting axonal regeneration within the injured spinal cord. A number of studies have indicated the ability of these cells to promote significant reactive sprouting of injured axons within the injured spinal cord, and in some cases restoration of functional abilities. However, the cellular and/or molecular mechanisms OECs use to achieve this are unclear. To investigate such mechanisms, we report for the first time the ability of OECs to promote post-injury neurite sprouting in an in vitro model of axonal injury. Using this model, we were able to differentiate between the direct and indirect mechanisms underlying the ability of OECs to promote neuronal recovery from injury. We noted that OECs appeared to act as a physical substrate for the growth of post-injury neurite sprouts. We also found that while post-injury sprouting was promoted most when OECs were allowed to directly contact injured neurons, physical separation using tissue culture inserts (1 mm pore size, permeable to diffusible factors but not cells) did not completely block the promoting properties of OECs, suggesting that they also secrete soluble factors which aid post-injury neurite sprouting. Furthermore, this in vitro model allowed direct observation of the cellular interactions between OECs and sprouting neurites using live-cell-imaging techniques. In summary, we found that OECs separately promote neurite sprouting by providing a physical substrate for growth and through the expression of soluble factors. Our findings provide new insight into the ability of OECs to promote axonal regeneration, and also indicate potential targets for manipulation of these cells to enhance their restorative ability.Received 19 January 2004; received after revision 8 March 2004: accepted 17 March 2004     

Cortisone sensitive T-cells in Peyer's patches

Summary Pretreatment of donor lymphoid cells with cortisone has been shown to depress the T-cell subpopulation responsible for cellular proliferation in the GVH reaction. A quantitative assay as well as the histological criteria of the GVH reaction have been used in this study to demonstrate the presence of cortisone-sensitive T-cells within the Peyer's patches as well as in the spleen and mesenteric lymph nodes in the rat.This work was supported by a grant of the Délégation Générale à la Recherche Scientifique et Technique (No. 74-7-0619).     

Effect of olfactory ensheathing cells on reactive astrocytes <Emphasis Type="Italic">in vitro</Emphasis>

Olfactory ensheathing cells have been used in several studies to promote repair in the injured spinal cord. However, cellular interaction between olfactory ensheathing cells and glial cells induced to be reactive in the aftermath of injury site has not been investigated. Using an in vitro model of astrogliosis, we show that reactive astrocytes expressed significantly less glial fibrillary acidic protein (GFAP) when cultured both in direct contact with olfactory ensheathing cells and when the two cell types were separated by a porous membrane. Immunofluorescence staining also suggested that reactive astrocytes showed decreased chondroitin sulfate proteoglycans in the presence of olfactory ensheathing cells, although the reduction was not statistically significant. No down-regulation of GFAP was observed when reactive astrocytes were similarly cultured with Schwann cells. Cell viability assay and bromodeoxyuridine uptake showed that proliferation of reactive astrocytes was significantly increased in the presence of olfactory ensheathing cells and Schwann cells. Received 27 February 2007; received after revision 30 March 2007; accepted 3 April 2007     

“Jnking” atherosclerosis

Numerous studies in animal models established a key role of the C-jun N-terminal kinase (JNK) family (JNK1, JNK2 and JNK3) in numerous pathological conditions, including cancer, cardiac hypertrophy and failure, neurodegenerative disorders, diabetes, arthritis and asthma. A possible function of JNK in atherosclerosis remained uncertain since conclusions have mainly been based on in vitro studies investigating endothelial cell activation, T-effector cell differentiation and proliferation of vascular smooth muscle cells, all of which represent crucial cellular processes involved in atherosclerosis. However, recent experiments demonstrated that macrophage-restricted deletion of JNK2 was sufficient to efficiently reduce atherosclerosis in mice. Furthermore, it has been shown that JNK2 specifically promotes scavenger receptor A-mediated foam cell formation, an essential step during early atherogenesis, which occurs when vascular macrophages internalize modified lipoproteins. Thus, specific inhibition of JNK2 activity may emerge as a novel and promising therapeutic approach to attenuate atheroma formation in the future. In this review, we discuss JNK-dependent cellular and molecular mechanisms underlying atherosclerosis. Received 9 June 2005; received after revision 18 July 2005; accepted 18 July 2005     

Polycystins and cellular Ca2+ signaling

The cystic phenotype in autosomal dominant polycystic kidney disease is characterized by a profound dysfunction of many cellular signaling patterns, ultimately leading to an increase in both cell proliferation and apoptotic cell death. Disturbance of normal cellular Ca²⁺ signaling seems to be a primary event and is clearly involved in many pathways that may lead to both types of cellular responses. In this review, we summarize the current knowledge about the molecular and functional interactions between polycystins and multiple components of the cellular Ca²⁺-signaling machinery. In addition, we discuss the relevant downstream responses of the changed Ca²⁺ signaling that ultimately lead to increased proliferation and increased apoptosis as observed in many cystic cell types.     

Regulation of the Hippo pathway in cancer biology

The Hippo tumor suppressor pathway, which is well conserved from Drosophila to humans, has emerged as the master regulator of organ size, as well as major cellular properties, such as cell proliferation, survival, stemness, and tissue homeostasis. The biological significance and deregulation of the Hippo pathway in tumorigenesis have received a surge of interest in the past decade. In the current review, we present the major discoveries that made substantial contributions to our understanding of the Hippo pathway and discuss how Hippo pathway components contribute to cellular signaling, physiology, and their potential implications in anticancer therapeutics.     

Myosin II in mechanotransduction: master and commander of cell migration, morphogenesis, and cancer

Mechanotransduction encompasses the role of mechanical forces in controlling cell behavior by activating signal transduction pathways. Most forces at a cellular level are caused by myosin II, which contracts and cross-links actin. Myosin II-dependent forces are transmitted through the actin cytoskeleton to molecular endpoints that promote specific cellular outcomes, e.g., cell proliferation, adhesion, or migration. For example, most adhesive and migratory phenomena are mechanically linked by a molecular clutch comprised of mechanosensitive scaffolds. Myosin II activation and mechanosensitive molecular mechanisms are finely tuned and spatiotemporally integrated to coordinate morphogenetic events during development. Mechanical events dependent on myosin II also participate in tumor cell proliferation, invasion, and metastatic dissemination. Specifically, tumor cells alter the mechanical properties of the microenvironment to create favorable conditions for proliferation and/or dissemination. These observations position myosin II-dependent force generation and mechanotransduction at the crossroads between normal development and cancer.     

Filamentous bodies in human glomerulonephritis

Summary Filamentous bodies have been identified in the glomerular cells of human kidney biopsies. These structures have a close morphological resemblance to ciliary rootlets, although the cells of the glomerular tuft only occasionally bear cilia. Their significance could be, as for cilia, of a cellular disdifferentiation of a pathological cellular proliferation.     

Filamentous bodies in human glomerulonephritis

Filamentous bodies have been identified in the glomerular cells of human kidney biopsies. These structures have a close morphological resemblance to ciliary rootlets, although the cells of the glomerular tuft only occasionally bear cilia. Their significance could be, as for cilia, of a cellular disdifferentiation of a pathological cellular proliferation.     

Ras proteins: paradigms for compartmentalised and isoform-specific signalling

Ras GTPases mediate a wide variety of cellular processes by converting a multitude of extracellular stimuli into specific biological responses including proliferation, differentiation and survival. In mammalian cells, three ras genes encode four Ras isoforms (H-Ras, K-Ras4A, K-Ras4B and N-Ras) that are highly homologous but functionally distinct. Differences between the isoforms, including their post-translational modifications and intracellular sorting, mean that Ras has emerged as an important model system of compartmentalised signalling and membrane biology. Ras isoforms in different subcellular locations are proposed to recruit distinct upstream and downstream accessory proteins and activate multiple signalling pathways. Here, we summarise data relating to isoform-specific signalling, its role in disease and the mechanisms promoting compartmentalised signalling. Further understanding of this field will reveal the role of Ras signalling in development, cellular homeostasis and cancer and may suggest new therapeutic approaches.