Retina stem cells, hopes and obstacles

Table 1 Stem cells in retinal diseases

Retinal disease	Type of SC used	Type of intervention	Clinical trial status	Results: Advantages and disadvantages	Ethical concerns
RP, AMD	Fetal RPCs[33,147-150]	Subretinal or intravitreal transplantation	Yes[40,151]	Rescue of PHRs and low risk of tumorigenesis. Able to differentiate into MGCs and retinal neurons; improvement of retinal sensitivity. Adverse effects: limited amount of cells and low tissue integration. Promising therapeutic treatment.	Little
RP, AMD, most retinal degenerations	PSCs and iPSCs	Reprogramed to iPSC[40]	Yes[40,200,293]	Potential replacement of damaged retinal cells. Low immunogenicity. Adverse effects: risk of teratoma development[40,50,156,160-163].	Little or none
				Genomic instability in iPSC. Further research still needed.
AMD, retinal degenerations	RPE	Transplantation of RPE sheets from human fetal eyes in AMD patients	Yes[204,283]	Substantial rescue of PHRs. Visual improvement[147,148].	Concerns about using human tissues
				Little or no evidences of draft rejection[33,203,204,281,285].
				Adverse effects: unwanted cell aggregation; lack of attachment; cases of anoikis[162,163].
AMD, stargardt disease	Human ESC-RPE	Injection of differentiated ESC-RPE cells in subretinal space[238]	Yes phase 1/2a trial[175,176]	Cells form monolayers and display typical RPE features[171-173].	Concerns about using human tissues
				Improvement of visual acuity. No tumorigenicity or rejection after 4 years[187].
				Cell sheets preserve RPE characteristics better than cell suspension[175-178]. Absence of serious adverse effects[131,188]. Effectiveness still uncertain.
AMD	iPSC-RPE	Autologous transplantation into an AMD patient of cell-sheets of RPE, differentiated from iPSC obtained from the skin’s patient[195]	Yes[195,199,200]	Preservation of main RPE features.	Important concerns about safety
				Long term survival of transplanted iPSC-RPE cells[196,199,200]. Visual acuity stable for 4 years[197,198].
				Presence of mutations in iPSCs[199]. Little immune rejection[202]. Adverse effects: Risk of tumorigenesis.
				Still pending to establish the adequate iPSC-RPE cells and the effectiveness of transplantation.
AMD, stargardt macular distrophy	human fetal SC	Transplantation of human fetal RPE cells into subretinal space	Yes[176,203]	Improvement of visual parameters.No immunosuppression; No restoring of retinal morphology; no expression of retinal markers[169,208]. Adverse effects: little graft rejection in patients with AMD.Further research still required to provide effective and safe treatments.	Concerns about using aborted human fetuses
Retinal degeneration	MGCs	Not established	No	Express most SC markers; potentially capable of retinal regeneration after reprogramming. Obstacles: gliosis, low regenerative potential.	Not determined
Retinal degeneration, retinal injuries and uveitis	Bone marrow (MSC) and hematopoietic SC	Intravitreal injection (in mouse models of RP)	No	Promote regeneration of different retinal cells[238,246-248]. Safety not determined.	Not determined

The use of different stem cells for treating retinal degenerations, such as retinal pigment or AMD, entails many advantages but also disadvantages and ethical concerns. SC: Stem cells; RP: Retinal pigment; AMD: Age-related macular degeneration; PHRs: Photoreceptors; MGCs: Müller glial cells; PSCs: Pluripotent stem cells; iPSCs: Induced pluripotent stem cells; RPE: Retinal pigment epithelial; ESC: Embryonic stem cells; MSC: Mesenchymal stem cells.