Myeloid progenitors differentiate into microglia and promote vascular repair in a model of ischemic retinopathy
Matthew R. Ritter, … , Michael I. Dorrell, Martin Friedlander
Matthew R. Ritter, … , Michael I. Dorrell, Martin Friedlander
Published December 1, 2006
Citation Information: J Clin Invest. 2006;116(12):3266-3276. https://doi.org/10.1172/JCI29683.
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Research Article

Myeloid progenitors differentiate into microglia and promote vascular repair in a model of ischemic retinopathy

Abstract

Vision loss associated with ischemic diseases such as retinopathy of prematurity and diabetic retinopathy are often due to retinal neovascularization. While significant progress has been made in the development of compounds useful for the treatment of abnormal vascular permeability and proliferation, such therapies do not address the underlying hypoxia that stimulates the observed vascular growth. Using a model of oxygen-induced retinopathy, we demonstrate that a population of adult BM–derived myeloid progenitor cells migrated to avascular regions of the retina, differentiated into microglia, and facilitated normalization of the vasculature. Myeloid-specific hypoxia-inducible factor 1α (HIF-1α) expression was required for this function, and we also demonstrate that endogenous microglia participated in retinal vascularization. These findings suggest what we believe to be a novel therapeutic approach for the treatment of ischemic retinopathies that promotes vascular repair rather than destruction.

Authors

Matthew R. Ritter, Eyal Banin, Stacey K. Moreno, Edith Aguilar, Michael I. Dorrell, Martin Friedlander

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Figure 6

Microglia participate in retinal vascularization.

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Microglia participate in retinal vascularization. Comparing C57BL/6J and...
Comparing C57BL/6J and BALB/cByJ strains revealed a difference in the number of CD11b+ microglia during the ischemic phase of OIR. (A) In whole mounts, both strains showed similar vaso-obliteration in the central retina at P12. However, at P17, there were dramatic differences in the vasculature, with C57BL/6J showing abundant neovascular tufts and little revascularization of the central retina. (B) C57BL/6J retinas contained fewer CD11b+ microglia over the course of 48 hours of ischemia compared with BALB/cByJ. The optic nerve head is positioned at the lower right in all images. (C) Quantification of CD11b+ microglia over time shows that C57BL/6J retinas had fewer microglia at P12 (0 hours) and less than half the number of microglia present in the retinas of BALB/cByJ mice at P14 (48 hours of ischemia). P ≤ 0.02 for BALB/cByJ versus C57BL/6J at all time points (n = 8–11). (D) Microglia depletion in C57BL/6J induced dramatic loss of preexisting microvasculature during retinal development. Injection of clodronate liposomes at P5 resulted in significant loss of CD11b+ microglia and capillary dropout at P8. Images depict similar locations in the central retina, with the optic nerve head at lower right. (E) Injection of clodronate liposomes into C57BL/6J at P2 caused significant depletion of CD11b+ microglia and dramatic disruption of the vasculature at P6 compared with control PBS liposome–treated fellow eye. Inset: Labeled liposomes (red) were taken up specifically by CD11b+ microglia (green) and not by GS lectin–labeled vascular cells (blue), nor any other CD11b– cells. Magnification, ×4 (A and E, top panels), ×10 (D and E, bottom panels), ×20 (B), ×60 (E, inset).