title: Molecular Mechanisms Mediating Retinal Reactive Gliosis Following Bone Marrow Mesenchymal Stem Cell Transplantation.
abstract: A variety of diseases lead to degeneration of retinal ganglion cells (RGCs) and their axons within the optic nerve resulting in loss of visual function. Although current therapies may delay RGC loss, they do not restore visual function or completely halt disease progression. Regenerative medicine has recently focused on stem cell therapy for both neuroprotective and regenerative purposes. However, significant problems remain to be addressed, such as the long-term impact of reactive gliosis occurring in the host retina in response to transplanted stem cells. The aim of this work was to investigate retinal glial responses to intravitreally transplanted bone marrow mesenchymal stem cells (BM-MSCs) to help identify factors able to modulate graft-induced reactive gliosis. We found in vivo that intravitreal BM-MSC transplantation is associated with gliosis-mediated retinal folding, upregulation of intermediate filaments, and recruitment of macrophages. These responses were accompanied by significant JAK/STAT3 and MAPK (ERK1/2 and JNK) cascade activation in retinal Muller glia. Lipocalin-2 (Lcn-2) was identified as a potential new indicator of graft-induced reactive gliosis. Pharmacological inhibition of STAT3 in BM-MSC cocultured retinal explants successfully reduced glial fibrillary acidic protein expression in retinal Muller glia and increased BM-MSC retinal engraftment. Inhibition of stem cell-induced reactive gliosis is critical for successful transplantation-based strategies for neuroprotection, replacement, and regeneration of the optic nerve.
authors.affiliation: Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Alessia
authors.initials: A
authors.lastname: Tassoni
authors.affiliation: Pfizer Neusentis, Granta Park, Cambridge, United Kingdom.
authors.forename: Alex
authors.initials: A
authors.lastname: Gutteridge
authors.affiliation: Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Barber
authors.affiliation: Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Osborne
authors.affiliation: Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom.|Cambridge NIHR Biomedical Research Centre, Cambridge, United Kingdom.|Eye Department, Addenbrooke's Hospital, Cambridge, United Kingdom.|Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Cambridge, United Kingdom.
authors.forename: Keith R
authors.initials: KR
authors.lastname: Martin
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology; D001854:Bone Marrow Cells / Q000166:cytology; D063928:Ependymoglial Cells / Q000473:pathology; D005911:Gliosis / Q000473:pathology / Q000628:therapy*; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells; D051379:Mice; D009457:Neuroglia / Q000473:pathology*; D009900:Optic Nerve / Q000473:pathology; D044968:Regenerative Medicine; D012160:Retina / Q000254:growth & development / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000473:pathology
keywords: Glia; Mesenchymal stem cells; Retina; Stem cell transplantation