SDF-1 is both necessary and sufficient to promote proliferative retinopathy
Jason M. Butler, … , Maria B. Grant, Edward W. Scott
Jason M. Butler, … , Maria B. Grant, Edward W. Scott
Published January 3, 2005
Citation Information: J Clin Invest. 2005;115(1):86-93. https://doi.org/10.1172/JCI22869.
View: Text | PDF
Article Stem cells

SDF-1 is both necessary and sufficient to promote proliferative retinopathy

Abstract

Diabetic retinopathy is the leading cause of blindness in working-age adults. It is caused by oxygen starvation in the retina inducing aberrant formation of blood vessels that destroy retinal architecture. In humans, vitreal stromal cell–derived factor–1 (SDF-1) concentration increases as proliferative diabetic retinopathy progresses. Treatment of patients with triamcinolone decreases SDF-1 levels in the vitreous, with marked disease improvement. SDF-1 induces human retinal endothelial cells to increase expression of VCAM-1, a receptor for very late antigen–4 found on many hematopoietic progenitors, and reduce tight cellular junctions by reducing occludin expression. Both changes would serve to recruit hematopoietic and endothelial progenitor cells along an SDF-1 gradient. We have shown, using a murine model of proliferative adult retinopathy, that the majority of new vessels formed in response to oxygen starvation originate from hematopoietic stem cell–derived endothelial progenitor cells. We now show that the levels of SDF-1 found in patients with proliferative retinopathy induce retinopathy in our murine model. Intravitreal injection of blocking antibodies to SDF-1 prevented retinal neovascularization in our murine model, even in the presence of exogenous VEGF. Together, these data demonstrate that SDF-1 plays a major role in proliferative retinopathy and may be an ideal target for the prevention of proliferative retinopathy.

Authors

Jason M. Butler, Steven M. Guthrie, Mehmet Koc, Aqeela Afzal, Sergio Caballero, H. Logan Brooks, Robert N. Mames, Mark S. Segal, Maria B. Grant, Edward W. Scott

×

Figure 4

Options: View larger image (or click on image) Download as PowerPoint
SDF-1 reduces occludin expression on ECs. HRECs were isolated from 2 sep...
SDF-1 reduces occludin expression on ECs. HRECs were isolated from 2 separate donors: (A) a 43-year-old donor and (B) a 53-year-old donor. The HRECs were cultured in EGM containing 10% FCS for 3 weeks in order to establish tight cellular junctions. The test cultures were treated for 2 days with either EGM with reduced serum (RS) of 1%, or with EGM and 1% FCS plus either 0.1 nM SDF-1 or 100 nM SDF. Cells were harvested in extraction buffer and equal quantities of total protein separated by SDS-polyacrylamide gels followed by transfer to nitrocellulose and immunoblotted for occludin and β-actin (loading control) levels.