title: CXCL12/SDF-1-Dependent Retinal Migration of Endogenous Bone Marrow-Derived Stem Cells Improves Visual Function after Pharmacologically Induced Retinal Degeneration.
abstract: Mobilized bone marrow-derived stem cells (BMSC) have been discussed as an alternative strategy for endogenous repair. Thereby, different approaches for BMSC mobilization have been pursued. Herein, the role of a newly discovered oligonucleotide for retinal homing and regeneration capability of BMSCs was investigated in the sodium iodate (NaIO3) model of retinal degeneration. Mobilization was achieved in GFP-chimera with NOX-A12, a CXC-motif chemokine ligand 12 (CXCL12)/stromal cell-derived factor 1 (SDF-1)-neutralizing L-aptamer. BMSC homing was directed by intravitreal SDF-1 injection. Visual acuity was measured using the optokinetic reflex. Paraffin cross sections were stained with hematoxylin and eosin for retinal thickness measurements. Immunohistochemistry was performed to investigate the expression of cell-specific markers after mobilization. A single dose of NOX-A12 induced significant mobilization of GFP+cells which were found in all layers within the degenerating retina. An additional intravitreal injection of SDF-1 increased migration towards the site of injury. Thereby, the number of BMSCs (Sca-1+) found in the damaged retina increased whereas a decrease of activated microglia (Iba-1+) was found. The mobilization led to significantly increased visual acuity. However, no significant changes in retinal thickness or differentiation towards retinal cell types were detected. Systemic mobilization by a single dose of NOX-A12 showed increased homing of BMSCs into the degenerated retina, which was associated with improved visual function when injection of SDF-1 was additionally performed. The redistribution of the cells to the site of injury combined with their observed beneficial effects support the endogenous therapeutic strategy for retinal repair.
authors.affiliation: Department of Ophthalmology, University Hospital, University of Bern, Freiburgstrasse 14, 3010, Bern, Switzerland. volker.enzmann@insel.ch.|Department of Clinical Research, University of Bern, Bern, Switzerland. volker.enzmann@insel.ch.
authors.forename: Volker
authors.identifier: 0000-0003-4384-4855
authors.initials: V
authors.lastname: Enzmann
authors.affiliation: Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Lecaudé
authors.affiliation: NOXXON Pharma AG, Berlin, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Kruschinski
authors.affiliation: NOXXON Pharma AG, Berlin, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Vater
mesh_terms: D000818:Animals; D052157:Aptamers, Nucleotide; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D054377:Chemokine CXCL12 / Q000008:administration & dosage / Q000494:pharmacology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D056965:Injections, Intraocular; D007452:Iodates; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012160:Retina / Q000166:cytology; D012162:Retinal Degeneration / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D014404:Tubulin / Q000378:metabolism; D014792:Visual Acuity / Q000187:drug effects
chemical_list: D052157:Aptamers, Nucleotide; D054377:Chemokine CXCL12; D005904:Glial Fibrillary Acidic Protein; D007452:Iodates; C587878:NOX-A12; D014404:Tubulin; C462941:beta3 tubulin, mouse; C528900:glial fibrillary astrocytic protein, mouse; D049452:Green Fluorescent Proteins; C032285:sodium iodate
keywords: Bone marrow-derived stem cells (BMSC); L-aptamer; Mobilization; NOX-A12; Olaptesed pegol; Retinal degeneration; Sodium iodate; Spiegelmer