Human umbilical tissue‐derived cells rescue retinal pigment epithelium dysfunction in retinal degeneration

• Published in: Stem cells (Dayton, Ohio) Vol. 34; no. 2; pp. 367 - 379
• Main Authors: Cao, Jing, Murat, Christopher, An, Weijun, Yao, Xiang, Lee, John, Santulli‐Marotto, Sandra, Harris, Ian R., Inana, George
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01-02-2016
• Subjects: Animals; Bridge molecules; Cell therapy; Coculture Techniques; Disease Models, Animal; Eye Proteins - biosynthesis; Growth factors; Humans; Ligands; Macular degeneration; Phagocytosis; Rats; Receptor tyrosine kinase; Retina; Retinal degeneration; Retinal Degeneration - metabolism; Retinal Degeneration - pathology; Retinal Degeneration - therapy; Retinal pigment epithelium; Retinal Pigment Epithelium - metabolism; Retinal Pigment Epithelium - pathology; Rodents; Umbilical Cord - metabolism; Umbilical Cord - pathology; Umbilical Cord - transplantation; Receptor tyrosine kinase; Retinal degeneration; Cell therapy; Bridge molecules; Phagocytosis; Retinal pigment epithelium
• ISSN: 1066-5099; 1549-4918
• DOI: 10.1002/stem.2239

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. Stem Cells 2016;34:367–379