Descrizione del progetto
Un modello in vitro della nicchia perivascolare
Il microambiente intorno ai capillari sanguigni è noto come nicchia perivascolare e svolge un ruolo importante in varie condizioni, tra cui la neuroinfiammazione. L’obiettivo del progetto B3M, finanziato dal Consiglio europeo della ricerca, è studiare la nicchia perivascolare dei vasi cerebrali ricreandola in vitro. Utilizzando idrogel con proprietà regolabili come substrato e le cellule endoteliali derivate da cellule staminali pluripotenti indotte, i ricercatori riprodurranno l’architettura e la funzione della nicchia perivascolare in vivo. Il sistema in vitro consentirà di studiare gli eventi cellulari e molecolari che determinano la penetrazione dei leucociti nella nicchia perivascolare e che portano alla neuroinfiammazione.
Obiettivo
In neuroinflammation leukocytes reside for several days in the perivascular niche of cerebral blood vessels - defined by the basal surface of the endothelium, the endothelial basement membrane (BM) and an outer parenchymal BM with associated astrocyte endfeet (Fig. 1) - a poorly studied site but of utmost fundamental and clinical relevance. This site is also emerging as harbouring genetically distinct resident cell populations, the function of which are unclear. BMs define the perivascular niche and the sealed nature of this compartment in an unknown manner. B3M will explore the perivascular niche of cerebral vessels. Using our new dextran-hydrogel with tuneable adhesive, stiffness and degradability properties and cerebral endothelial cells derived from induced pluripotent stem cells (iPSC) we will recreate the subendothelial site; we will sequentially increase its complexity to reflect the in vivo spatial arrangement of cells and BMs, within the most correctly mimicked environmental properties, in a system that permits perfusion with immune cells and live imaging. Parallel ex vivo and synthetic approaches will further break down the complexity of this site into discrete steps and using multiscale imaging of new split-cre transgenic mice we will track, target and profile perivascular cells lacking BM receptors. Studies to date on leukocyte entry into the brain focus on endothelial properties or immune cell behaviour with little consideration of the 3D relationship between cellular and BM barriers and their functional interdependence. My unique knowledge on extracellular matrix structure/function of cerebral vessels and leukocyte migration into the brain, allows me to identify key elements of the perivascular niche and how they can be mimicked in vitro and targeted in vivo. B3M’s cross-disciplinary approach will decipher cellular and molecular events occurring after leukocyte penetration of the endothelium in the perivascular niche, shedding light on a black box.
Campo scientifico
Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
HORIZON-ERC - HORIZON ERC GrantsIstituzione ospitante
48149 MUENSTER
Germania