Adult retinal stem cells revisited

Abstract

Recent advances in retinal stem cell research have raised the possibility that these cells have the potential to be used to repair or regenerate diseased retina. Various cell sources for replacement of retinal neurons have been identified, including embryonic stem cells, the adult ciliary epithelium, adult Müller stem cells and induced pluripotent stem cells (iPS). However, the true stem cell nature of the ciliary epithelium and its possible application in cell therapies has now been questioned, leaving other cell sources to be carefully examined as potential candidates for such therapies. The need for identification of the ontogenetic state of grafted stem cells in order to achieve their successful integration into the murine retina has been recognized. However, it is not known whether the same requirements may apply to achieve transplant cell integration into the adult human eye. In addition, the existence of natural barriers for stem cell transplantation, including microglial accumulation and abnormal extracellular matrix deposition have been demonstrated, suggesting that several obstacles need to be overcome before such therapies may be implemented. This review addresses recent scientific developments in the field and discusses various strategies that may be potentially used to design cell based therapies to treat human retinal disease.

Keywords: Human retina; Müller stem cells; adult stem cells; ciliary marginal zone; regeneration; transplantation..

Fig. (1)

Schematic diagram showing the anatomy of the most anterior neural retina and ciliary body of the adult human eye. A non-laminated region, similar to that seen in fish and amphibians and known as the ciliary marginal zone (CMZ) is present in fish and amphibians throughout life [33-36]. A similar region has been identified in the early postnatal life of avians [38] and rodents [55], as well as in young primates [22] and human adults [25].

Fig. (2)

Expression of neural progenitor markers in the non-laminated region (ciliary margin-like zone) of the adult human retina. (A) Confocal image of adult human retina showing intense expression of Nestin (green) in the most peripheral region adjacent to the ciliary body (asterisk). Pigmented (solid arrow) and non-pigmented (segmented arrow) ciliary epithelium do not express Nestin in situ [25]. (B) Confocal image of non-laminated anterior retina showing expression of the Müller cell marker CRALBP (green) and the progenitor marker CHX10 (red).

Fig. (3)

A population of Müller glia from the adult human retina express neural stem cell characteristics in vitro. (A) Cells cultured in the absence of extracellular matrix and growth factors display a characteristic glial morphology. In contrast, cells cultured in the presence of extracellular matrix and FGF2 for 5 days acquire a neural morphology with characteristic axon-like processes (red arrows). (B) Müller stem cells in culture express the retinal progenitor markers CHX10, SOX2 and intermediate filament nestin.