Multimodal Delivery of Isogenic Mesenchymal Stem Cells Yields Synergistic Protection from Retinal Degeneration and Vision Loss

We previously demonstrated that subretinal injection (SRI) of isogenic mesenchymal stem cells (MSCs) reduced the severity of retinal degeneration in Royal College of Surgeons rats in a focal manner. In contrast, intravenous MSC infusion (MSC(IV)) produced panoptic retinal rescue. By combining these treatments, we now show that MSC(IV) supplementation potentiates the MSC(SRI)‐mediated rescue of photoreceptors and visual function. Electrophysiological recording from superior colliculi revealed 3.9‐fold lower luminance threshold responses (LTRs) and 22% larger functional rescue area from combined treatment compared with MSC(SRI) alone. MSC(IV) supplementation of sham (saline) injection also improved LTRs 3.4‐fold and enlarged rescue areas by 27% compared with saline alone. We confirmed the involvement of MSC chemotaxis for vision rescue by modulating C‐X‐C chemokine receptor 4 activity before MSC(IV) but without increased retinal homing. Rather, circulating platelets and lymphocytes were reduced 3 and 7 days after MSC(IV), respectively. We demonstrated MSC(SRI)‐mediated paracrine support of vision rescue by SRI of concentrated MSC‐conditioned medium and assessed function by electroretinography and optokinetic response. MSC‐secreted peptides increased retinal pigment epithelium (RPE) metabolic activity and clearance of photoreceptor outer segments ex vivo, which was partially abrogated by antibody blockade of trophic factors in concentrated MSC‐conditioned medium, or their cognate receptors on RPE. These data support multimodal mechanisms for MSC‐mediated retinal protection that differ by administration route and synergize when combined. Thus, using MSC(IV) as adjuvant therapy might improve cell therapies for retinal dystrophy and warrants further translational evaluation. Stem Cells Translational Medicine 2017;6:444–457