Retinal pigment epithelium development, plasticity, and tissue homeostasis

Abstract

The retinal pigment epithelium (RPE) is a simple epithelium interposed between the neural retina and the choroid. Although only 1 cell-layer in thickness, the RPE is a virtual workhorse, acting in several capacities that are essential for visual function and preserving the structural and physiological integrities of neighboring tissues. Defects in RPE function, whether through chronic dysfunction or age-related decline, are associated with retinal degenerative diseases including age-related macular degeneration. As such, investigations are focused on developing techniques to replace RPE through stem cell-based methods, motivated primarily because of the seemingly limited regeneration or self-repair properties of mature RPE. Despite this, RPE cells have an unusual capacity to transdifferentiate into various cell types, with the particular fate choices being highly context-dependent. In this review, we describe recent findings elucidating the mechanisms and steps of RPE development and propose a developmental framework for understanding the apparent contradiction in the capacity for low self-repair versus high transdifferentiation.

Keywords: RPE; age-related macular degeneration; development; regeneration; retina; self-repair; transdifferentiation.

Fig. 1

Regulation of early eye and RPE development by extracellular signals and transcription factors. The eye field is initiated in the anterior neural plate by induction of eye field transcription factors: Pax6, Tll, Rx, T/Tbx3, Six3/6. Rx may be upregulated cooperatively by Otx2 and Sox2 that are broadly expressed in the anterior neural plate. Additional interaction with extracellular pathways (BMP, Wnt, sonic hedgehog) separate the eye field from other brain regions. Eye field transcription factors promote Lhx2 expression that acts as a competence factor to allow patterning of the optic vesicle. Otx2, Mitf (possibly induced by TGFb-like signals), and Pax6 are initially present throughout the optic vesicle, however Mitf is then downregulated by Vsx2 in the presumptive retina domain, which is initiated by FGF signals. Otx2 may further suppress expression of FGF and Sox2 to support RPE formation. In the optic cup, additional factors such as Wnt, hedgehog, retinoids, Gas1, CoupTFs, BMP4, Notch and Vax stabilize the RPE fate and promote differentiation into RPE subdomains. For more details, see text. A: anterior, P: posterior.

Fig. 2. Limitations in RPE transdifferentiation activity

The temporally restricted transdifferentiation capacity of the RPE (#1) may be determined by cell-intrinsic factors including the stage of development in which RPE progenitors still retain the competence to activate a retinal program (RPE/retina bipotentiality, #2), or the stage of development in which RPE cells are undergoing cellular differentiation and tissue growth (RPE differentiation/expansion). Cell-extrinsic influences (#3) may further limit the period of transdifferentiation potential by exposing RPE cells to inhibitory signals or blocking access to transdifferentiation-promoting signals. Although not shown, cell-extrinsic influences may also play a prominent role in limiting proliferative potential and fate plasticity in the mature RPE.