title: Lipo-chitin oligosaccharides, plant symbiosis signalling molecules that modulate mammalian angiogenesis in vitro.
abstract: Lipochitin oligosaccharides (LCOs) are signaling molecules required by ecologically and agronomically important bacteria and fungi to establish symbioses with diverse land plants. In plants, oligo-chitins and LCOs can differentially interact with different lysin motif (LysM) receptors and affect innate immunity responses or symbiosis-related pathways. In animals, oligo-chitins also induce innate immunity and other physiological responses but LCO recognition has not been demonstrated. Here LCO and LCO-like compounds are shown to be biologically active in mammals in a structure dependent way through the modulation of angiogenesis, a tightly-regulated process involving the induction and growth of new blood vessels from existing vessels. The testing of 24 LCO, LCO-like or oligo-chitin compounds resulted in structure-dependent effects on angiogenesis in vitro leading to promotion, or inhibition or nil effects. Like plants, the mammalian LCO biological activity depended upon the presence and type of terminal substitutions. Un-substituted oligo-chitins of similar chain lengths were unable to modulate angiogenesis indicating that mammalian cells, like plant cells, can distinguish between LCOs and un-substituted oligo-chitins. The cellular mode-of-action of the biologically active LCOs in mammals was determined. The stimulation or inhibition of endothelial cell adhesion to vitronectin or fibronectin correlated with their pro- or anti-angiogenic activity. Importantly, novel and more easily synthesised LCO-like disaccharide molecules were also biologically active and de-acetylated chitobiose was shown to be the primary structural basis of recognition. Given this, simpler chitin disaccharides derivatives based on the structure of biologically active LCOs were synthesised and purified and these showed biological activity in mammalian cells. Since important chronic disease states are linked to either insufficient or excessive angiogenesis, LCO and LCO-like molecules may have the potential to be a new, carbohydrate-based class of therapeutics for modulating angiogenesis.
authors.affiliation: Research School of Biology, Plant Science Division, College of Medicine, Biology and the Environment, Australian National University, Canberra, ACT, Australia.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Djordjevic
authors.affiliation: John Curtin School of Medical Research, College of Medicine, Biology and the Environment, Australian National University, Canberra, ACT, Australia.
authors.forename: Anna
authors.initials: A
authors.lastname: Bezos
authors.affiliation: John Curtin School of Medical Research, College of Medicine, Biology and the Environment, Australian National University, Canberra, ACT, Australia.
authors.lastname: Susanti
authors.affiliation: University Grenoble Alpes, CERMAV, Grenoble, France CNRS, CERMAV, Grenoble, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Marmuse
authors.affiliation: University Grenoble Alpes, CERMAV, Grenoble, France CNRS, CERMAV, Grenoble, France.
authors.forename: Hugues
authors.initials: H
authors.lastname: Driguez
authors.affiliation: University Grenoble Alpes, CERMAV, Grenoble, France CNRS, CERMAV, Grenoble, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Samain
authors.affiliation: University Paris Sud, Institut de Chimie Moléculaire et des Matériaux d'Orsay, Orsay, France, and Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles du CNRS, Gif-sur-Yvette, France.
authors.forename: Boris
authors.initials: B
authors.lastname: Vauzeilles
authors.affiliation: University Paris Sud, Institut de Chimie Moléculaire et des Matériaux d'Orsay, Orsay, France, and Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles du CNRS, Gif-sur-Yvette, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Beau
authors.affiliation: Research School of Biology, Plant Science Division, College of Medicine, Biology and the Environment, Australian National University, Canberra, ACT, Australia.
authors.forename: Farzaneh
authors.initials: F
authors.lastname: Kordbacheh
authors.affiliation: Research School of Biology, Plant Science Division, College of Medicine, Biology and the Environment, Australian National University, Canberra, ACT, Australia.
authors.forename: Barry G
authors.initials: BG
authors.lastname: Rolfe
authors.affiliation: Ferrier Research Institute, Victoria University of Wellington, Lower Hutt Wellington, New Zealand.
authors.forename: Ralf
authors.initials: R
authors.lastname: Schwörer
authors.affiliation: Ferrier Research Institute, Victoria University of Wellington, Lower Hutt Wellington, New Zealand.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Daines
authors.affiliation: The Centre for Integrative Legume Research, The University of Queensland, St Lucia, Brisbane, Queensland, Australia.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Gresshoff
authors.affiliation: John Curtin School of Medical Research, College of Medicine, Biology and the Environment, Australian National University, Canberra, ACT, Australia.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Parish
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000215:Acylation / Q000187:drug effects; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D004187:Disaccharides / Q000737:chemistry / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D016023:Integrins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000737:chemistry / Q000494:pharmacology*; D008322:Mammals / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011916:Rats, Inbred F344; D015398:Signal Transduction / Q000187:drug effects*; D013025:Glycine max / Q000737:chemistry*; D013559:Symbiosis / Q000187:drug effects*
chemical_list: D004187:Disaccharides; D016023:Integrins; D008070:Lipopolysaccharides; C023023:lipid-linked oligosaccharides; C032438:chitobiose