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CXCL12/SDF-1-Dependent Retinal Migration of Endogenous Bone Marrow-Derived Stem Cells Improves Visual Function after Pharmacologically Induced Retinal Degeneration

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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.

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Acknowledgements

The authors thank Monika Kilchenmann, Agathe Duda and Federica Bisignani for their excellent technical assistance. This work was partly supported by grants from the Swiss National Science Foundation (310000-119894), the Velux Foundation, NOXXON Pharma AG and the Berne University Research Foundation.

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Authors and Affiliations

  1. Department of Ophthalmology, University Hospital, University of Bern, Freiburgstrasse 14, 3010, Bern, Switzerland

    Volker Enzmann

  2. Department of Clinical Research, University of Bern, Bern, Switzerland

    Volker Enzmann & Stéphanie Lecaudé

  3. NOXXON Pharma AG, Berlin, Germany

    Anna Kruschinski & Axel Vater

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  1. Volker Enzmann
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  2. Stéphanie Lecaudé
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Correspondence to Volker Enzmann.

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AV and AK are employees of NOXXON Pharma which holds or has applied for patents relating to the content of the manuscript.

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All animals were treated according to the ARVO statement for the use of animals in vision und ophthalmic research and after governmental approval.

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Enzmann, V., Lecaudé, S., Kruschinski, A. et al. CXCL12/SDF-1-Dependent Retinal Migration of Endogenous Bone Marrow-Derived Stem Cells Improves Visual Function after Pharmacologically Induced Retinal Degeneration. Stem Cell Rev and Rep 13, 278–286 (2017). https://doi.org/10.1007/s12015-016-9706-0

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