iPSC-derived retinal pigment epithelium: an in vitro platform to reproduce key cellular phenotypes and pathophysiology of retinal degenerative diseases

Abstract

Retinal pigment epithelium (RPE) atrophy is a significant cause of human blindness worldwide, occurring in polygenic diseases such as age-related macular degeneration (AMD) and monogenic diseases such as Stargardt diseases (STGD1) and late-onset retinal degeneration (L-ORD). The patient-induced pluripotent stem cells (iPSCs)-derived RPE (iRPE) model exhibits many advantages in understanding the cellular basis of pathological mechanisms of RPE atrophy. The iRPE model is based on iPSC-derived functionally mature and polarized RPE cells that reproduce several features of native RPE cells, such as phagocytosis of photoreceptor outer segments (POS) and replenishment of visual pigment. When derived from patients, iRPE are able to recapitulate critical cellular phenotypes of retinal degenerative diseases, such as the drusen-like sub-RPE deposits in the L-ORD and AMD models; lipid droplets and cholesterol accumulation in the STGD1 and AMD models. The iRPE model has helped discover the unexpected role of RPE in understanding retinal degenerative diseases, such as a cell-autonomous function of ABCA4 in STGD1. The iRPE model has helped uncover the pathological mechanism of retinal degenerative diseases, including the roles of alternate complement cascades and oxidative stress in AMD pathophysiology, abnormal POS processing in STGD1 and L-ORD, and its association with lipid accumulation. These studies have helped better understand-the role of RPE in retinal degenerative diseases, and molecular mechanisms underlying RPE atrophy, and have provided a basis to discover therapeutics to target RPE-associated diseases.

Keywords: RPE atrophy; cell disease model; iPSCs-derived RPE; retinal degenerative diseases.

Graphical Abstract

Figure 1.

The potential pathological mechanisms of retinal degenerative diseases in iRPE model. (A) Schematic presentation of iPSC-RPE generation. (B) The images of transmission electron microscope from the healthy (left panel) and CC-HS treated (right panel) iRPE cells. The healthy iRPE cells show fully polarization, including tight junctions between neighboring RPE cells, basally located nucleus, apically located melanosome granules, and an extensive network for apical processes, while the CC-HS treated iRPE cells show typical intra and subRPE lipid deposits. (C) Signal pathways involved in RPE atrophy of retinal degenerative diseases. In iRPE model, the Stargadt disease gene ABCA4 regulates POS processing to reduce lipid deposits in autocrine manner, the L-ORD disease gene CTRP5 is required for lipid metabolism and mitochondrial activity via blocking the activity of AMPK to reduce lipid deposits and oxidative stress, and the AMD high-risk variant CFH(Y402H) targets to NFkB and inhibits autophagy through activating complement cascades to induce drusen formation. STGD1, Stargadt disease type 1; AMD, age-related macular degeneration; L-ORD, late-onset of retinal degeneration; POS, photoreceptor outer segment.