Advances in cell therapies using stem cells/progenitors as a novel approach for neurovascular repair of the diabetic retina

Abstract

Background: Diabetic retinopathy, a major complication of diabetes mellitus, is a leading cause of sigh-loss in working age adults. Progressive loss of integrity of the retinal neurovascular unit is a central element in the disease pathogenesis. Retinal ischemia and inflammatory processes drive interrelated pathologies such as blood retinal barrier disruption, fluid accumulation, gliosis, neuronal loss and/or aberrant neovascularisation. Current treatment options are somewhat limited to late-stages of the disease where there is already significant damage to the retinal architecture arising from degenerative, edematous and proliferative pathology. New preventive and interventional treatments to target early vasodegenerative and neurodegenerative stages of the disease are needed to ensure avoidance of sight-loss.

Main body: Historically, diabetic retinopathy has been considered a primarily microvascular disease of the retina and clinically it is classified based on the presence and severity of vascular lesions. It is now known that neurodegeneration plays a significant role during the pathogenesis. Loss of neurons has been documented at early stages in pre-clinical models as well as in individuals with diabetes and, in some, even prior to the onset of clinically overt diabetic retinopathy. Recent studies suggest that some patients have a primarily neurodegenerative phenotype. Retinal pigment epithelial cells and the choroid are also affected during the disease pathogenesis and these tissues may also need to be addressed by new regenerative treatments. Most stem cell research for diabetic retinopathy to date has focused on addressing vasculopathy. Pre-clinical and clinical studies aiming to restore damaged vasculature using vasoactive progenitors including mesenchymal stromal/stem cells, adipose stem cells, CD34⁺ cells, endothelial colony forming cells and induced pluripotent stem cell derived endothelial cells are discussed in this review. Stem cells that could replace dying neurons such as retinal progenitor cells, pluripotent stem cell derived photoreceptors and ganglion cells as well as Müller stem cells are also discussed. Finally, challenges of stem cell therapies relevant to diabetic retinopathy are considered.

Conclusion: Stem cell therapies hold great potential to replace dying cells during early and even late stages of diabetic retinopathy. However, due to the presence of different phenotypes, selecting the most suitable stem cell product for individual patients will be crucial for successful treatment.

Keywords: Adult stem cells; DME; Diabetic retinopathy; Endothelial progenitor cells; Induced pluripotent stem cells; Macular ischemia; Microvascular disease; Neurodegeneration; PDR; Retinal progenitor cells.

Fig. 1

Ultra-widefield fundus images showing five stages of Diabetic Retinopathy (DR) according to the international classification of DR

Fig. 2

Structure of the retina and overview of various stem cells that may be used to restore damaged cells in Diabetic Retinopathy. ECFC Endothelial colony forming cells; MAC Myeloid angiogenic cells; MSC Mesenchymal stromal/stem cells; ASC Adipose stromal/stem cells; iPSC Induced pluripotent stem cells; RPC Retinal progenitor cells. Schematic created with BioRender.com