Adult Stem Cell Therapeutics in Diabetic Retinopathy

Abstract

Diabetic retinopathy (DR), a complication of diabetes, is one of the leading causes of blindness in working-age adults. The pathology of the disease prevents the endogenous stem cells from participating in the natural repair of the diseased retina. Current treatments, specifically stem cell therapeutics, have shown variable efficacy in preclinical models due to the multi-faceted nature of the disease. Among the various adult stem cells, mesenchymal stem cells, especially those derived from adipose tissue and bone marrow, have been explored as a possible treatment for DR. This review summarizes the current literature around the various adult stem cell treatments for the disease and outlines the benefits and limitations of the therapeutics that are being explored in the field. The paracrine nature of adipose stem cells, in particular, has been highlighted as a potential solution to the lack of a homing and conducive environment that poses a challenge to the implantation of exogenous stem cells in the target tissue. Various methods of mesenchymal stem cell priming to adapt to a hostile retinal microenvironment have been discussed. Current clinical trials and potential safety concerns have been examined, and the future directions of stem cell therapeutics in DR have also been contemplated.

Keywords: CD140b; CD34; adipose stem cells; diabetes; hypoxia; inflammation; mesenchymal; paracrine; retina.

Figure 1

Current regenerative cell therapy efforts in diabetic retinopathy. A variety of stem cells including bone marrow mesenchymal stem cells (BM-MSC), adipose stem cells (ASC), and induced pluripotent stem cells (iPSC) have been considered in diabetic retinopathy. Arrows point to the stem cells that either differentiates into endothelial or pericyte like cells to replace lost cells or provide trophic support (Please refer to the text for more details). The image was adapted with permission from Springer Nature: Regenerative Medicine—from Protocol to Patient. Regenerative Therapies for Retinopathy. Periasamy R., Gangaraju R. (2016), designed using Adobe Photoshop and drawn in Adobe Illustrator.

Figure 2

Intravitreal injection of CD140b+ ASC localize on the host retinal vasculature and improved visual function better than the CD140b- ASC. Unilateral retinal I/R was done in adult Lewis rats by transiently elevating the IOP for 1 h. On day 7 of reperfusion, the animals were randomized to receive intravitreal CD140b+ASC, CD140b-ASC (1000 cells/eye) or saline injections. (A) Confocal image of the retinal flat mount of retinal I/R injury rat with CD140b-ASC (left) and CD140b+ASC (right) after 21 days. Arrows point to maurocalcine labeled ASC (red). Blood vessels were identified using Griffonia Simplicifolia Lectin I (GSL I) isolectin B4 (green) and counterstained with DAPI-labeled nucleated cells (blue). 20× magnification. Inset box is the enlarged portion showing CD140b+ASC on the vasculature. (B) Retinal I/R resulted in a reduction in “b” wave amplitude, which was improved by CD140b+ ASC compared with CD140b- ASC (25cd.ms², p < 0.0001). Data shown is a representation of 3–7 animals/group.