Bone marrow–derived stem cells target retinal astrocytes and can promote or inhibit retinal angiogenesis

Abstract

Adult bone marrow (BM) contains cells capable of differentiating along hematopoietic (Lin(+)) or non-hematopoietic (Lin(-)) lineages. Lin(-) hematopoietic stem cells (HSCs) have recently been shown to contain a population of endothelial precursor cells (EPCs) capable of forming blood vessels. Here we show that intravitreally injected Lin(-) BM cells selectively target retinal astrocytes, cells that serve as a template for both developmental and injury-associated retinal angiogenesis. When Lin(-) BM cells were injected into neonatal mouse eyes, they extensively and stably incorporated into forming retinal vasculature. When EPC-enriched HSCs were injected into the eyes of neonatal rd/rd mice, whose vasculature ordinarily degenerates with age, they rescued and maintained a normal vasculature. In contrast, normal retinal angiogenesis was inhibited when EPCs expressing a potent angiostatic protein were injected. We have demonstrated that Lin(-) BM cells and astrocytes specifically interact with one another during normal angiogenesis and pathological vascular degeneration in the retina. Selective targeting with Lin(-) HSC may be a useful therapeutic approach for the treatment of many ocular diseases.

Vascular endothelial growth factor in eye disease

“…Studies in a model of ischemic retinopathy have shown that bone marrow-derived hematopoietic stem cells participate in retinal neovascularization (Grant et al, 2002). Investigations using cell-based gene therapy in the mouse OIR model showed that these cells can rescue and stabilize degenerating vessels, and the cells can inhibit new vessel formation in a mouse model of retinal degeneration (Otani et al, 2002). By contrast, studies using animal models for ocular vascular damage, including diabetes, ischemia/reperfusion injury and OIR, have shown that cells from normal donors attach and assimilate into the existing vasculature.…”

Stem Cells for Retinal Replacement Therapy

“…For stem cells with endothelial potential, retinal revascularization can be observed directly through the pupil, making the retina a good model system for studying stem cell-mediated CNS revascularization in general. Restoration of vasculature located on the inner retinal surface by BMSCs is a rational approach toward rescue of retinal neurons lost in retinal vascular disorders, such as diabetic retinopathy [52][53][54]. Injection of BMSCs into the eye improves retinal circulation, enhances survival of outer retinal neurons, and rescues vision in both ischemic and nonischemic mouse models of retinal degeneration [53,55].…”

Possible mechanisms of retinal function recovery with the use of cell therapy with bone marrow-derived stem cells

“…Although this approach showed a dramatic rescue effect, there was a limitation in that intravitreally injected bone marrow (BM)-derived stem cells were effectively incorporated into the retina only during an early, postnatal developmental stage, but not in adult mice. Directly injected exogenous Lin -HSCs only targeted activated astrocytes that are observed in neonatal mice or in an injury-induced model in the adult (20)(21)(22) .…”