Novel Cell-Based and Tissue Engineering Approaches for Induction of Angiogenesis as an Alternative Therapy for Diabetic Retinopathy

Abstract

Diabetic retinopathy (DR) is the most frequent microvascular complication of long-term diabetes and the most common cause of blindness, increasing morbidity in the working-age population. The most effective therapies for these complications include laser photocoagulation and anti-vascular endothelial growth factor (VEGF) intravitreal injections. However, laser and anti-VEGF drugs are untenable as a final solution as they fail to address the underlying neurovascular degeneration and ischemia. Regenerative medicine may be a more promising approach, aimed at the repair of blood vessels and reversal of retinal ischemia. Stem cell therapy has introduced a novel way to reverse the underlying ischemia present in microvascular complications in diseases such as diabetes. The present review discusses current treatments, their side effects, and novel cell-based and tissue engineering approaches as a potential alternative therapeutic approach.

Keywords: diabetic retinopathy; ischemia; stem cell; vascular regeneration; vascular tissue engineering.

Figure 1

Illustrative pictures of non-proliferative diabetic retinopathy (DR) (NPDR) (left) and proliferative DR (PDR) (right). In early-stage NPDR, damaged blood vessels begin to leak extra fluid and blood into the eye. In PDR, many retinal blood vessels are closed, disrupting blood flow. In response to hypoxia, new blood vessels are generated (neovascularization), which are abnormal and ineffective. Illustration with permission from https://maxivisioneyehospital.wordpress.com.

Figure 2

Angiogenesis regulation. Angiogenesis includes two phases. (a) In the activation phase, the basement membrane is degraded by angiogenic stimulus (VEGF, bFGF, and TGF-ß) (b) and tip cells invade the tissue by extending filopodia. Stalk cells proliferate and extend, and new branches join in tip-cell-tip-cell fusion. (c) Lastly, in the resolution phase, endothelial cells (ECs) stop proliferating and mature by re-formation of basement membrane (d) and obtain a quiescent phenotype which is called phalanx EC. Illustration with permission from [37]. (e) VEGF signalling induces Dll4 expression in tip cells and consecutively, Dll4 activates Notch signalling in stalk cells. This results in reducing stalk-cell sensitivity to VEGF stimulation, which in turn suppresses the tip cell phenotype. Illustration with permission from [38,39].

Figure 3

In vitro culture of endothelial progenitor cells (EPCs); early vs late outgrowth. EPCs are grown from whole peripheral blood mononuclear cells. Early EPCs are obtained from short term culturing (4–7 days) on fibronectin. A small population of EPCs when plated for >14 days is called late-outgrowth EPC (or ECFC) and demonstrate an increased capacity for proliferation and blood vessel formation. Illustration with permission from [64].

Figure 4

Various sources of stem cells. ES cells are isolated from the inner cell mass (ICM) of the blastocyst and are considered pluripotent. Primordial germ cells are derived from embryonic germ cells and are pluripotent. Fetal stem cells are derived from the developing foetus and are pluripotent or multipotent. All stem cells derived after birth are adult stem cells (ADS). These cells have limited potential and are usually multipotent. Cord blood derived stem cells occupy a niche between ES cell and ADS. These have been categorized to be pluripotent and display some ES cell-like properties. Illustration from www.stemcellresearch.org/testimony/images/20040929prentice.htm.