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 support vision. However, very promisingtransplantation achievements suggest that thisfield is advancing and that cell engraftment is apotential therapy that needs to be exploited for retinaldegenerations. The literature available so far suggeststhat the outcome of transplantation is affectedby several variables, such as the properties and thehomogeneity of transplanted cells, the maturationstage, the site of injection and the extracellularmatrix in the host tissue. Recent evidences showedthat engraftment in a degenerating retina can be moreeffective if post-mitotic photoreceptor precursors areemployed rather then very immature and naïve retinalprogenitors or fully differentiated photoreceptors(5). This suggests that a cell needs to be a photoreceptorprecursor in order to be able to respond tolocal cues in the host tissue and successfully integrateinto a retina. The availability of cells at differentdevelopmental times can open new transplantationstrategies to be employed for the degenerating retina.Finally, we need to consider that none of thepapers addressing cell transplants and published sofar provided a compelling evidence of functionalityof engrafted cells. The definition of photoreceptordifferentiation was based on expression of specificgenes and proteins. Functionality and response tolight was never demonstrated neither in vitro nor invivo after transplantation. This is a limitation ofmost of the studies of retinal transplants and it ismostly due to the low numbers of integrated cellsfor which functionality cannot be measured by classicalERG and VEP analyses.Over the next five years we will continue to seeprogresses in the field of stem cell differentiation.Certainly, ethical issues will influence this research.Furthermore, many biological and technologicalhurdles have to be overcome before cell therapiescan be brought to patients. I believe that the firstvery important problem will be the identification ofthe human cell source suitable to give rise to ahomogenous culture of differentiated functionalphotoreceptors. Secondly a cell graft in the humanretina will require a large number of cells in orderto be effective in restoring vision. Availability of thecell source and possibility of expansion of the cellsin vitro before transplantation will be high prioritiesin this field of research.
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|Anno di pubblicazione:||2008|
|Titolo:||Stem cells as prospective therapeutic tools for retinal degeneration|
|Appare nelle tipologie:||Articolo su rivista|
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