Human neural progenitor cell treatment modulates phagocytosis signaling in a rodent model for retinal degeneration

Abstract

Purpose : Retinal degenerative diseases (RDDs) are characterized by the loss of photoreceptors in the retina leading to irreversible vision loss. Stem/progenitor cell transplantation provides therapeutic promise for treating RDDs, though the modes of action of cell based therapies are largely unknown. Our previous studies have shown that a subretinal injection of human neural progenitor cells (hNPCs) into Royal College of Surgeons (RCS) rats with inherited retinal degeneration aided in visual function and photoreceptor preservation. The purpose of this study was to identify the gene expression changes in the RCS retinal tissue following treatment with hNPCs.

Methods : hNPCs were subretinally transplanted into RCS rats at an early stage of degeneration under immunosuppression. Visual function was examined by optokinetic response, and photoreceptor survival was determined by histology staining. Rat retinal tissue was collected for RNA-seq transcriptome analysis, and in silico analysis was performed. Gene expression was validated by qRT-PCR, and signaling analysis was examined by immunofluorescent staining.

Results : hNPCs subretinally injected into RCS rats at early stages of degeneration significantly preserved both photoreceptors and visual function, as compared with sham control animals. Bioinformatic analyses of RNA-seq data identified 1,263 differentially expressed genes between sham surgery RCS (RCS^sham) and sham treated wild-type Long Evans (LE^sham) rats, and 283 differentially expressed genes between RCS^sham and hNPC-treated RCS (RCS^hNPCs) rats. Pathway analysis identified three affected pathways that are rescued in RCS^hNPCs retina. These pathways include integrin, phospholipase C, and Rho Family GTPase signaling, which all play roles in phagocytosis. Immunohistochemicial analysis detected increased presence of macrophages and microglia in RCS^sham, while RCS^hNPCs had similar amounts of macrophages and microglia as LE^sham in areas with photoreceptor survival.

Conclusions : hNPCs offered preservation of vision after a single subretinal injection into a rodent model of retinal degeneration. Retinal tissue gene expression changes following injection of hNPCs correlate with modulation of phagocytosis signaling by macrophages and microglia. Understanding the host retinal tissue response to hNPC treatment may aid in future therapies for treating RDDs.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.