Stem cells as source for retinal pigment epithelium transplantation

Abstract

Inherited maculopathies, age related macular degeneration and some forms of retinitis pigmentosa are associated with impaired function or loss of the retinal pigment epithelium (RPE). Among potential treatments, transplantation approaches are particularly promising. The arrangement of RPE cells in a well-defined tissue layer makes the RPE amenable to cell or tissue sheet transplantation. Different cell sources have been suggested for RPE transplantation but the development of a clinical protocol faces several obstacles. The source should provide a sufficient number of cells to at least recover the macula area. Secondly, cells should be plastic enough to be able to integrate in the host tissue. Tissue sheets should be considered as well, but the substrate on which RPE cells are cultured needs to be carefully evaluated. Immunogenicity can also be an obstacle for effective transplantation as well as tumorigenicity of not fully differentiated cells. Finally, ethical concerns may represent drawbacks when embryo-derived cells are proposed for RPE transplantation. Here we discuss different cell sources that became available in recent years and their different properties. We also present data on a new source of human RPE. We provide a protocol for RPE differentiation of retinal stem cells derived from adult ciliary bodies of post-mortem donors. We show molecular characterization of the in vitro differentiated RPE tissue and demonstrate its functionality based on a phagocytosis assay. This new source may provide tissue for allogenic transplantation based on best matches through histocompatibility testing.

Features specific to retinal pigment epithelium cells derived from three-dimensional human embryonic stem cell cultures — a new donor for cell therapy

“…The intercellular connections in 3D-RPE cells had important functions in the formation of the blood-retinal barrier, cell polarity, and intracellular communication [2]. Although SD-RPE cells also formed some characteristic ultrastructure of native RPE cells, we did not detect bipolar location of caveolaes and intercellular structures such as adherences junction and desmosomes.…”

“…RPE can secrete nutrition factors, phagocytose photoreceptor outer segment (POS) and is involved in the formation of the blood-retinal barrier; the pigment granules in RPE cells have light-absorbing and anti-oxidative stress functions [1]. Dysfunction of RPE usually results in secondary degeneration of photoreceptor cells, thus causing sight-threaten diseases, including age-related macular degeneration (AMD) and Stargardt's macular dystrophy [2]. Unfortunately, no effective treatment is found for curing these retinal degeneration diseases currently.…”

“…The former method uses defined factors to target the induction of ESCs into RPE cells [16–18]. The directed differentiation procedures, however, required very long culture times and, so far, did not show enough advancement compared to the spontaneous method to justify their application for therapeutic purposes [2, 14]. The recently reported 3D ESC cultures method, based on 3D embryoid body differentiation protocol, generates self-organizing optic cups mimicking normal development of embryonic retinal tissue [15, 19].…”

Use of Human Embryonic Stem Cells in the Treatment of Age-Related Macular Degeneration

“…AMD, a progressive neurodegenerative condition primarily affects the retinal pigmented epithelium (RPE), secondarily resulting in degeneration of photoreceptors in people ≥ 50 years [2].…”

“…Stem cells withability to self-renew and differentiate into any cell type has been the promising source for AMD treatment. Stem cells that have been explored in animal models for the treatment of AMD include embryonic stem cells (ESCs) and human induced pluripotent stem cells (iPSCs) and mesenchymal stem cells (MSCs) [2,6]. In our previous studies we have shown the improvement in the patient's condition suffering from cerebral palsy, cortical visual impairment (CVI), Lyme's disease, spinocerebellar ataxia, Friedreich's ataxia and spinal cord injury after human embryonic stem cells (hESCs) therapy [7][8][9][10][11][12].…”