SDF-1 is both necessary and sufficient to promote proliferative retinopathy.
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.
Butler
Jason M
JM
Program in Stem Cell Biology and Regenerative Medicine, University of Florida Shands Cancer Center, Gainesville, Florida, USA.
Guthrie
Steven M
SM
Koc
Mehmet
M
Afzal
Aqeela
A
Caballero
Sergio
S
Brooks
H Logan
HL
Mames
Robert N
RN
Segal
Mark S
MS
Grant
Maria B
MB
Scott
Edward W
EW
D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000328:Adult; D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D003930:Diabetic Retinopathy / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007511:Ischemia / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D015861:Retinal Neovascularization / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D017186:Titrimetry; D014221:Triamcinolone / Q000627:therapeutic use
D000305:Adrenal Cortex Hormones; D000906:Antibodies; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D014221:Triamcinolone