title: Human umbilical tissue-derived cells rescue retinal pigment epithelium dysfunction in retinal degeneration.
abstract: Retinal pigment epithelium (RPE) cells perform many functions crucial for retinal preservation and vision. RPE cell dysfunction results in various retinal degenerative diseases, such as retinitis pigmentosa and age-related macular degeneration (AMD). Currently, there are no effective treatments for retinal degeneration except for a small percentage of individuals with exudative AMD. Cell therapies targeting RPE cells are being developed in the clinic for the treatment of retinal degeneration. Subretinal injection of human umbilical tissue-derived cells (hUTC) in the Royal College of Surgeons (RCS) rat model of retinal degeneration was shown to preserve photoreceptors and visual function. However, the precise mechanism remains unclear. Here, we demonstrate that hUTC rescue phagocytic dysfunction in RCS RPE cells in vitro. hUTC secrete receptor tyrosine kinase (RTK) ligands brain-derived neurotrophic factor (BDNF), hepatocyte growth factor (HGF), and glial cell-derived neurotrophic factor (GDNF), as well as opsonizing bridge molecules milk-fat-globule-epidermal growth factor 8 (MFG-E8), growth arrest-specific 6 (Gas6), thrombospondin (TSP)-1, and TSP-2. The effect of hUTC on phagocytosis rescue in vitro is mimicked by recombinant human proteins of these factors and is abolished by siRNA-targeted gene silencing in hUTC. The bridge molecules secreted from hUTC bind to the photoreceptor outer segments and facilitate their ingestion by the RPE. This study elucidates novel cellular mechanisms for the repair of RPE function in retinal degeneration through RTK ligands and bridge molecules, and demonstrates the potential of using hUTC for the treatment of retinal degenerative diseases.
authors.affiliation: Janssen Research and Development, LLC, Spring House, Pennsylvania, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Cao
authors.affiliation: Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Murat
authors.affiliation: Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors.forename: Weijun
authors.initials: W
authors.lastname: An
authors.affiliation: Janssen Research and Development, LLC, San Diego, California, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Yao
authors.affiliation: Janssen Research and Development, LLC, Spring House, Pennsylvania, USA.
authors.forename: John
authors.initials: J
authors.lastname: Lee
authors.affiliation: Janssen Research and Development, LLC, Spring House, Pennsylvania, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Santulli-Marotto
authors.affiliation: Janssen Research and Development, LLC, Spring House, Pennsylvania, USA.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Harris
authors.affiliation: Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors.forename: George
authors.initials: G
authors.lastname: Inana
mesh_terms: D000818:Animals; D018920:Coculture Techniques; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000096:biosynthesis; D006801:Humans; D051381:Rats; D012162:Retinal Degeneration / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D055213:Retinal Pigment Epithelium / Q000378:metabolism* / Q000473:pathology; D014470:Umbilical Cord / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation
chemical_list: D005136:Eye Proteins
keywords: Bridge molecules; Cell therapy; Phagocytosis; Receptor tyrosine kinase; Retinal degeneration; Retinal pigment epithelium