title: Early Inflammatory Responses Following Cell Grafting in the CNS Trigger Activation of the Subventricular Zone: A Proposed Model of Sequential Cellular Events.
abstract: While multiple rodent preclinical studies, and to a lesser extent human clinical trials, claim the feasibility, safety, and potential clinical benefit of cell grafting in the central nervous system (CNS), currently only little convincing knowledge exists regarding the actual fate of the grafted cells and their effect on the surrounding environment (or vice versa). Our preceding studies already indicated that only a minor fraction of the initially grafted cell population survives the grafting process, while the surviving cell population becomes invaded by highly activated microglia/macrophages and surrounded by reactive astrogliosis. In the current study, we further elaborate on early cellular and inflammatory events following syngeneic grafting of eGFP(+) mouse embryonic fibroblasts (mEFs) in the CNS of immunocompetent mice. Based on obtained quantitative histological data, we here propose a detailed mathematically derived working model that sequentially comprises hypoxia-induced apoptosis of grafted mEFs, neutrophil invasion, neoangiogenesis, microglia/macrophage recruitment, astrogliosis, and eventually survival of a limited number of grafted mEFs. Simultaneously, we observed that the cellular events following mEF grafting activates the subventricular zone neural stem and progenitor cell compartment. This proposed model therefore further contributes to our understanding of cell graft-induced cellular responses and will eventually allow for successful manipulation of this intervention.
authors.affiliation: Experimental Cell Transplantation Group, Laboratory of Experimental Hematology, University of Antwerp, Wilrijk, Belgium.
authors.forename: Jelle
authors.initials: J
authors.lastname: Praet
authors.forename: Eva
authors.initials: E
authors.lastname: Santermans
authors.forename: Jasmijn
authors.initials: J
authors.lastname: Daans
authors.forename: Debbie
authors.initials: D
authors.lastname: Le Blon
authors.forename: Chloé
authors.initials: C
authors.lastname: Hoornaert
authors.forename: Herman
authors.initials: H
authors.lastname: Goossens
authors.forename: Niel
authors.initials: N
authors.lastname: Hens
authors.forename: Annemie
authors.initials: A
authors.lastname: Van der Linden
authors.forename: Zwi
authors.initials: Z
authors.lastname: Berneman
authors.forename: Peter
authors.initials: P
authors.lastname: Ponsaerts
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002478:Cells, Cultured; D002490:Central Nervous System / Q000276:immunology / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000637:transplantation; D017930:Genes, Reporter; D006085:Graft Survival; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D000860:Hypoxia; D007249:Inflammation; D020547:Lateral Ventricles / Q000166:cytology*; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism; D008954:Models, Biological; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000276:immunology*
chemical_list: D049452:Green Fluorescent Proteins