title: Variable behavior and complications of autologous bone marrow mesenchymal stem cells transplanted in experimental autoimmune encephalomyelitis.
abstract: Autologous bone marrow stromal cells (BMSCs) offer significant practical advantages for potential clinical applications in multiple sclerosis (MS). Based on recent experimental data, a number of clinical trials have been designed for the intravenous (IV) and/or intrathecal (ITH) administration of BMSCs in MS patients. Delivery of BMSCs in the cerebrospinal fluid via intracerebroventricular (ICV) transplantation is a useful tool to identify mechanisms underlying the migration and function of these cells. In the current study, BMSCs were ICV administered in severe and mild EAE, as well as naive animals; neural precursor cells (NPCs) served as cellular controls. Our data indicated that ICV-transplanted BMSCs significantly ameliorated mild though not severe EAE. Moreover, BMSCs exerted significant anti-inflammatory effect on spinal cord with concomitant reduced axonopathy only in the mild EAE model. BMSCs migrated into the brain parenchyma and, depending on their cellular density, within brain parenchyma formed cellular masses characterized by focal inflammation, demyelination, axonal loss and increased collagen-fibronectin deposition. These masses were present in 64% of ICV BMASC-transplanted severe EAE animals whereas neither BMSCs transplanted in mild EAE cases nor the NPCs exhibited similar behavior. BMSCs possibly exerted their fibrogenic effect via both paracrine and autocrine manner, at least partly due to up-regulation of connective tissue growth factor (CTGF) under the trigger of TGFb1. Our findings are of substantial relevance for clinical trials in MS, particularly regarding the possibility that ICV transplanted BMSCs entering the inflamed central nervous system may exhibit - under conditions - a local pathology of yet unknown consequences.
authors: Laboratory of Experimental Neurology and Neuroimmunology, 2nd Department of Neurology, AHEPA University Hospital, Aristotle University of Thessaloniki, Macedonia, Greece. grigoria@med.auth.gr
authors: Nikolaos
authors: N
authors: Grigoriadis
authors: Athanasios
authors: A
authors: Lourbopoulos
authors: Roza
authors: R
authors: Lagoudaki
authors: Josa-Maria
authors: JM
authors: Frischer
authors: Eleni
authors: E
authors: Polyzoidou
authors: Olga
authors: O
authors: Touloumi
authors: Constantina
authors: C
authors: Simeonidou
authors: Georgia
authors: G
authors: Deretzi
authors: Jannis
authors: J
authors: Kountouras
authors: Evangelia
authors: E
authors: Spandou
authors: Konstantia
authors: K
authors: Kotta
authors: Georgios
authors: G
authors: Karkavelas
authors: Nikolaos
authors: N
authors: Tascos
authors: Hans
authors: H
authors: Lassmann
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001921:Brain / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000401:mortality / Q000473:pathology / Q000601:surgery*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics; D007276:Injections, Intraventricular / Q000009:adverse effects; D007371:Interferon-gamma / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation / Q000009:adverse effects*; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000502:physiology / Q000637:transplantation; D012720:Severity of Illness Index; D013116:Spinal Cord / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014182:Transplantation, Autologous / Q000009:adverse effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D049452:Green Fluorescent Proteins; D007371:Interferon-gamma