Protéoglycane | EPFL Graph Search

Un protéoglycane est une glycoprotéine, combinaison d'une protéine et d'un glycosaminoglycane (GAG). L'association entre les deux types de chaîne s'effectue essentiellement dans l'appareil de Golgi, mais également au niveau du réticulum endoplasmique d'une cellule. La proportion de glucides des protéoglycanes peut atteindre 95 %. Ceux-ci se présentant sous la forme d'une ou plusieurs chaînes de glycosaminoglycanes non ramifiées. Les chaînes de sucres sont très longues mais pas ramifiées. Ils sont O-glycosylés, se lient à l'acide aminé sérine à l'extrémité OH. Les protéoglycanes peuvent être soit transportés à l'extérieur de la cellule par exocytose (s'intégrant alors à la matrice extracellulaire sous forme de chondroïtine-sulfate, kératane-sulfate, héparane-sulfate, dermatane-sulfate, etc.), soit entrer dans la constitution de la membrane plasmique ou du glycocalyx, jouant alors un rôle dans les relations cellule-matrice. Les PG (protéoglycanes) ont des compositions et poids moléculaire très variés et sont hétérogènes au niveau de leur structure et de leur fonction. Les protéoglycanes sont des composants essentiels de la matrice extracellulaire. Ce sont des pièges à eau qui sont importants pour les propriétés mécaniques des tissus cartilagineux par exemple. Les héparane sulfates peuvent avoir un rôle dans la signalisation : ce sont des co-récepteurs pour les FGF (Fibroblast Growth Factor). Les protéoglycanes jouent aussi un rôle dans la diffusion des molécules de signalisation (Wnt, Shh), ou bien en interagissant avec des inhibiteurs (Noggin). Protéoglycanes sécrétés (liste non exhaustive) : Aggrécane (impliqué dans l'adhérence cellulaire ; il peut être lysé lors d'inflammations cellulaires) présent dans le cartilage. Biglycane (impliqué dans l'adhérence cellulaire) Décorine (le plus petit protéoglycane), ubiquitaire Fibromoduline Serglycine (intracellulaire) Versicane, associé aux parois des vaisseaux Perlécane (excrété par le fibroblaste), on le trouve notamment au niveau des membranes basales dans la lamina densa.

Effects of dynamic environments on extracellular morphogen gradients

Mark Fleury

Tissue morphogenesis and remodeling is often orchestrated by cell-secreted proteins, referred to as morphogens that can trigger cellular responses in addition to modifying the local extracellular matrix (ECM). Of specific interest is the distribution of cell secreted proteins in the cell microenvironment and how this distribution can lead to varied responses. Morphogens often provide directional cues, and as such their specific distribution is critical to the signaling that they induce, in other words cells are sensitive to morphogen gradients and not just absolute amounts. Natural cellular environments in native tissue involve three dimensional ECM and are typically subjected to dynamic conditions such as interstitial flow (IF). Despite the importance of the extracellular environment in signaling, very little is known regarding the effects of mechanical stresses and subtle interstitial flows. This thesis examines the role of IF on morphogen gradients using mass transport models to elucidate mechanisms responsible for several specific biological phenomena including in vitro capillary formation and lymphatic metastasis of tumor cells. In vitro capillary formation had been shown in our lab to be separately enhanced by bound VEGF alone and slow IF alone, with the combination of these two conditions resulting in marked increase in organization. Using our computational model we were able to propose a novel mechanistic model to explain this synergy. Specifically showed how, through the combined effects of IF and matrix-bound growth factors, cells could create their own biased chemokine gradients without recourse to internal amplification methods. This process, which we have termed "autologous chemotaxis," drives directional signaling and migration in the direction of flow. This can occur even at very low Peclet numbers, when diffusion still dominates the overall transport, but convection changes the shape of the gradient, which is what a cell responds to. We then examined the effects of IF on tumor cell migration to explore a novel mechanism of lymphatic metastasis. Tumors often produce high amounts of proteoglycans creating a microenvironment is rich in morphogen binding sites, and tumors are also a source of interstitial flow due to their leaky vasculature. The lymphatic system drains interstitial fluid, therefore IF is always directed toward lymphatic capillaries. The lymphatic system is also a common route of tumor metastasis, which is what lead us to study the role of IF mediated chemotaxis. A computational model of an in vitro tumor invasion assay was constructed that predicted tumor cell migration that was in very good agreement with the in vitro experimental results. This phenomenon was further studied by modeling an in vivo geometry and examining the factors controlling autologous gradient formation in a physiological setting. In conclusion, we have demonstrated the importance of convective mass transport at very low flow velocities in a biological context. While these velocities are low enough that the convective effects would typically be ignored, their subtle effects on pericellular mass transport can be translated into relevant and observable morphogenic responses.

EPFL2007

Effects of dynamic environments on extracellular morphogen gradients

Mark Fleury

EPFL2007