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Adult hematopoietic stem cells provide functional hemangioblast activity during retinal neovascularization

Abstract

Adults maintain a reservoir of hematopoietic stem cells that can enter the circulation to reach organs in need of regeneration. We developed a novel model of retinal neovascularization in adult mice to examine the role of hematopoietic stem cells in revascularizing ischemic retinas. Adult mice were durably engrafted with hematopoietic stem cells isolated from transgenic mice expressing green fluorescent protein. We performed serial long-term transplants, to ensure activity arose from self-renewing stem cells, and single hematopoietic stem-cell transplants to show clonality. After durable hematopoietic engraftment was established, retinal ischemia was induced to promote neovascularization. Our results indicate that self-renewing adult hematopoietic stem cells have functional hemangioblast activity, that is, they can clonally differentiate into all hematopoietic cell lineages as well as endothelial cells that revascularize adult retina. We also show that recruitment of endothelial precursors to sites of ischemic injury has a significant role in neovascularization.

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Figure 1: FACS analysis of purified HSCs and multilineage reconstitution.
Figure 2: Induction of pre-retinal neovascularization containing gfp+ endothelial cells.
Figure 3: Fluorescence micrographs of vascular development in C57BL/6.gfp chimeric mice that underwent retinal ischemia. The mice were perfused with rhodamine-labeled dextran, and flat mounts of the retina were examined by standard and confocal fluorescence microscopy.
Figure 4: Neovascular tufts in serial or single HSC transplants.

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Acknowledgements

We thank S. Sharkis for advice on single-cell transplants. E.W.S. is a scholar of the Leukemia and Lymphoma Society of America. This work was supported by grants EY012601 and EY007739 (to M.B.G.) and grants CA72769 and DK52558 (to E.W.S.).

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Correspondence to Maria B. Grant or Edward W. Scott.

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Grant, M., May, W., Caballero, S. et al. Adult hematopoietic stem cells provide functional hemangioblast activity during retinal neovascularization. Nat Med 8, 607–612 (2002). https://doi.org/10.1038/nm0602-607

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