Mobilizing endogenous stem cells for retinal repair

Abstract

Irreversible vision loss is most often caused by the loss of function and subsequent death of retinal neurons, such as photoreceptor cells-the cells that initiate vision by capturing and transducing signals of light. One reason why retinal degenerative diseases are devastating is that, once retinal neurons are lost, they don't grow back. Stem cell-based cell replacement strategy for retinal degenerative diseases are leading the way in clinical trials of transplantation therapy, and the exciting findings in both human and animal models point to the possibility of restoring vision through a cell replacement regenerative approach. A less invasive method of retinal regeneration by mobilizing endogenous stem cells is, thus, highly desirable and promising for restoring vision. Although many obstacles remain to be overcome, the field of endogenous retinal repair is progressing at a rapid pace, with encouraging results in recent years.

Figure 1

Sources of endogenous retinal stem cells. The retina has been shown to contain a population of endogenous stem cells, including Müller cells in neural retina, retinal pigment epithelium and ciliary epithelium cells in the ciliary margin zone.

Figure 2

Müller cells, retinal pigment epithelium and Ciliary epithelium cells are reported as retinal stem cells for retinal repair in mammals. (A) Latent Müller cells are stimulated or suppressed to re-enter the cell cycle by different factors (green or red boxes). Müller cells can be induced to proliferate by growth factors and transcription factors listed in the green boxes and differentiate into various retinal cell types. Modification of epigenetic factors may also contribute to the regulation of the stem cell potency of Müller cells. (B) It has been shown that in vitro, ciliary epithelium cells isolated from mature retina can be stimulated (green box) or suppressed (red box) to re-enter the cell cycle, differentiating into new neurons, including photoreceptors (PR), and glia cells. (C) Retinal pigment epithelium has also been shown to possess the ability to proliferate and transdifferentiate into retinal neurons, but the neurogenic potential of these cells in mammals are fairly restricted and appear to be deficient in the regulatory elements that are required for induction of transdifferentiation. EGF: Epidermal Growth Factor; FGF: Fibroblast Growth Factor; PEDF: Pigment Epithelium-Derived Factor; α-AA: α-Aminoadipic Acid; Ascl1: Achaete-Scute Complex-like 1; Pax6: Paired Box Gene 6; Brn2: Brain-2; PRC2: polycomb repressive complex-2; HDAC: Dnmts: DNA methyltransferases; RPC: Retinal Progenitor cell; PR: Photoreceptor; RPE: Retinal Pigment Epithelium; HC: Horizontal cell; BP: Bipolar cell; MC: Müller cell; AC: Amacrine cell; RGC: Retinal Ganglion cell; NFL: Nerve Fiber layer