Stem cells as prospective therapeutic tools for retinal degeneration

In the recent years stem cells are attracting muchinterest as prospective therapies for treating humandiseases and injury. Degenerative retinal diseasessuch as Retinitis Pigmentosa (RP) and Age RelatedMacular Dystrophy (AMD) have a dramatic socioeconomicimpact in our society. RP is a geneticallyheterogeneous disease and, up to now, around 34genes have been associated with it. On the otherhand, both genetic and environmental factors cooperateas cause of AMD. Due to genetic and functionaldiversity of the involved proteins, the molecularmechanisms underlying the different forms ofretinal degeneration are still not well understood.Limited knowledge on molecular processes leadingto photoreceptor loss hampers therapeutic interventionthat is still lagging behind and mutation independentapproaches are therefore seen as morepracticable approaches to restore vision. Amongthese methods, transplantation of in vitro culturedphotoreceptors is drawing a lot of attention.Cells with retinal progenitor characteristics havebeen isolated with the objective to develop replacementtherapies for the retina. Retinal progenitorscan be purified from the embryonic retina and inducedto differentiate into photoreceptors and otherretinal neuronal cell types. Importantly, stem cellshave been identified in the marginal region of theadult eye and retinal stem cells can be derived andcultured in vitro as pigmented neurospheres fromthe adult murine and human ciliary body (1) and iris(2). Of note, isolation of stem cells from the ciliarybody has been reported from eyes of donors aged upto 70 years old, indicating the possibility of usingeye bank tissues to obtain stem cells for regenerativetherapy. Secondly, stem cells derived from theadult ciliary body possess very good potentialitiesto give rise to high percentages of photoreceptorlikecells (3). In the last years several importantissues have been the focus of research in this field.A first aspect is the source of suitable human cells.Secondly, the cell source should be cultured underappropriate conditions in the absence of feederlayers, FBS, uncharacterized matrigel that can induceexpression of immunogenic antigens. Third, thecultures should be as less heterogeneous as possibleavoiding cells taking different fates other than photoreceptors.This opens several problems that needto be solved in order to develop a system that can betranslated to patients: priorities will be amplificationof the cells in culture to increase the amount ofphotoreceptor progenitors apt for cell transplantation.Secondly, we need to devise a differentiationand selection system to purify photoreceptors fromRPE and other cell types that may differentiate invitro. The most important obstacle to a therapeuticallyefficient retinal cells transplant is the availabilityof high amounts of cells necessary to restoresight. Because of the limited availability of cellsfrom human adult tissues, embryonic stem (ES)cells are, therefore, also seen as a possible source ofphotoreceptors. Several attempts to generate retinalneurons from ES cells have been reported. Themost recent of these papers showed differentiationof Rhodopsin expressing cells from human ES cellsby treatment with a defined formulated medium (4).Previous studies reported differentiation of ES cellsinto photoreceptor-like cells, however they werebased on co-culture experiments with embryonic oradult retinal tissue. These methods were far fromtherapeutic applicability because avoidance of animalderived additives to the culture medium is arequirement to translate protocols to patients.ARCH SOC ESP OFTALMOL 2008; 83: 397-400To date, transplantation studies have not providedcompelling evidence on the maturation of engraftedcells to photoreceptors and their integration into retinalnetworks to suppor