Cell Sources for Retinal Regeneration: Implication for Data Translation in Biomedicine of the Eye

Abstract

The main degenerative diseases of the retina include macular degeneration, proliferative vitreoretinopathy, retinitis pigmentosa, and glaucoma. Novel approaches for treating retinal diseases are based on cell replacement therapy using a variety of exogenous stem cells. An alternative and complementary approach is the potential use of retinal regeneration cell sources (RRCSs) containing retinal pigment epithelium, ciliary body, Müller glia, and retinal ciliary region. RRCSs in lower vertebrates in vivo and in mammals mostly in vitro are able to proliferate and exhibit gene expression and epigenetic characteristics typical for neural/retinal cell progenitors. Here, we review research on the factors controlling the RRCSs' properties, such as the cell microenvironment, growth factors, cytokines, hormones, etc., that determine the regenerative responses and alterations underlying the RRCS-associated pathologies. We also discuss how the current data on molecular features and regulatory mechanisms of RRCSs could be translated in retinal biomedicine with a special focus on (1) attempts to obtain retinal neurons de novo both in vivo and in vitro to replace damaged retinal cells; and (2) investigations of the key molecular networks stimulating regenerative responses and preventing RRCS-related pathologies.

Keywords: intrinsic cell sources; ophthalmotherapy; regulatory network; retinal degenerative diseases; retinal regeneration.

Figure 1

Potential endogenous cell sources for retinal regeneration (summarized data). RCZCs—cells of the retina ciliary zone; RPECs—retinal pigment epithelial cells; CBCs—cells of the ciliary body; MGCs—Müller glial cells.

Figure 2

Structure of the retina and retinal compartments involved in degenerative diseases. MGCs—Müller glial cells, AMD—age-related macular degeneration, PVR—proliferative vitreoretinopathy, RP—retinitis pigmentosa.

Figure 3

Schematic representation of AMD-related changes in the eye. (A)—normal eye; (B)—“dry” AMD; (C)—“wet” AMD. Ph—photoreceptors, BV—blood vessels, BM—Bruch membrane; RPE—retinal pigment epithelium.

Figure 4

Schematic illustration of PVR development. (A)—Normal eye. BM—Bruch’s membrane, RPE—retinal pigment epithelium, NR—neural retina. (B)—RPE at the beginning of the epithelial– mesenchymal transition. RPE-TCs—RPE-derived transforming cells. (C)—Epiretinal membrane (ERM) formation. (D)—Morphological changes of RPE cells during the epithelial–mesenchymal transition. MMPs—Matrix metalloproteases.

Figure 5

Changes occurring in the MGC population under conditions of retinal damage. (A)—MGCs in the structure of normal retina; (B)—MGC hypertrophy and proliferation in conditions of reactive gliosis; (C)—MGC reprogramming and proliferation during retinal regeneration in vivo and after directed stimulation in vitro; (D)—MGC-derived retinal cell precursors emerging during retinal regeneration in vivo and after directed stimulation in vitro; (E)—retinal neurons formed from MGC-derived retinal cell precursors. See more detailed description in the text.