title: Multimodal Delivery of Isogenic Mesenchymal Stem Cells Yields Synergistic Protection from Retinal Degeneration and Vision Loss.
abstract: 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 (MSCIV) produced panoptic retinal rescue. By combining these treatments, we now show that MSCIVsupplementation potentiates the MSCSRI-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 MSCSRIalone. MSCIVsupplementation 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 MSCIVbut without increased retinal homing. Rather, circulating platelets and lymphocytes were reduced 3 and 7 days after MSCIV, respectively. We demonstrated MSCSRI-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 MSCIVas adjuvant therapy might improve cell therapies for retinal dystrophy and warrants further translational evaluation. Stem Cells Translational Medicine 2017;6:444-457.
authors.affiliation: Board of Governors Regenerative Medicine Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bakondi
authors.affiliation: Board of Governors Regenerative Medicine Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Girman
authors.affiliation: Board of Governors Regenerative Medicine Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Lu
authors.affiliation: Board of Governors Regenerative Medicine Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Shaomei
authors.initials: S
authors.lastname: Wang
mesh_terms: D000818:Animals; D002465:Cell Movement; D002469:Cell Separation; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism; D004195:Disease Models, Animal; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000502:physiology*; D019899:Paracrine Communication; D010587:Phagocytosis; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism / Q000473:pathology; D051381:Rats; D012160:Retina / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D058499:Retinal Dystrophies / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D055213:Retinal Pigment Epithelium / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D013997:Time Factors; D014185:Transplantation, Isogeneic; D014786:Vision Disorders / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D014785:Vision, Ocular
chemical_list: D054377:Chemokine CXCL12
keywords: Age-related macular degeneration; Immunosuppression; Mesenchymal stem cell transplantation; Retinal pigment epithelium; Retinitis pigmentosa; Stromal derived factor-1α; Translational research; Trophic factor receptors