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MB Grant, S Caballero, PE Spoerri, EE Scott; Adult Hematopoietic Stem Cells Provide Functional Hemangioblast Activity During Retinal Neovascularization . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1928.
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Purpose: Adult animals and humans maintain a reservoir of hematopoietic stem cells (HSC) or progenitors that can enter the circulation and reach organs that need regeneration. The existence in adults of a common progenitor of both endothelial cells and hematopoietic cells, termed the hemangioblast, has been postulated but not proven. We developed a novel model of preretinal and intravitreal neovascularization in adult mice to examine the potential role of HSC and validate the contribution of hemangioblasts to re-vascularizing ischemic retina. Methods: Adult recipient mice (n=14) were durably engrafted with highly purified (Sca-1+/Lin-) HSC isolated from transgenic mice expressing green fluorescent protein (gfp). Serial transplants (n=5) were performed in which lethally irradiated hosts were provided with enriched bone marrow HSC from mice that had undergone primary transplants. After durable multilineage hematopoietic reconstitution was established, retinal ischemia was induced to promote neovascularization. Confocal microscopy and Factor VIII immunohistochemistry were used to image all retinas and validate the origin of gfp+ cells as endothelial cells. Results: In addition to resident endothelial cell proliferation, HSC were recruited to sites of ischemic injury, were incorporated into newly formed vascular tufts in all retinas, and repopulated all blood lineages in these mice. The mice serially transplanted with HSC also demonstrated functional hemangioblast activity, and showed the ability of HSC to expand and self-renew, thus satisfying the definition of a stem cell. Conclusion: Highly purified and durably engrafted bone marrow-derived HSC were shown to differentiate into endothelial cells at sites of ischemia-induced retinal neovascularization. These results suggest that adult HSC represent a potential therapeutic resource for modifying ischemia-induced retinal vascular diseases such as diabetic retinopathy and retinopathy of prematurity.
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