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Bone marrow–derived stem cells target retinal astrocytes and can promote or inhibit retinal angiogenesis

Nature Medicine volume 8, pages 1004–1010 (2002)Cite this article

Abstract

Adult bone marrow (BM) contains cells capable of differentiating along hematopoietic (Lin+) or non-hematopoietic (Lin−) lineages. Lin− hematopoietic stem cells (HSCs) have recently been shown to contain a population of endothelial precursor cells (EPCs) capable of forming blood vessels. Here we show that intravitreally injected Lin− BM cells selectively target retinal astrocytes, cells that serve as a template for both developmental and injury-associated retinal angiogenesis. When Lin− BM cells were injected into neonatal mouse eyes, they extensively and stably incorporated into forming retinal vasculature. When EPC-enriched HSCs were injected into the eyes of neonatal rd/rd mice, whose vasculature ordinarily degenerates with age, they rescued and maintained a normal vasculature. In contrast, normal retinal angiogenesis was inhibited when EPCs expressing a potent angiostatic protein were injected. We have demonstrated that Lin− BM cells and astrocytes specifically interact with one another during normal angiogenesis and pathological vascular degeneration in the retina. Selective targeting with Lin− HSC may be a useful therapeutic approach for the treatment of many ocular diseases.

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Figure 1: Characterization of retinal vascular development and BM-derived HSC.
Figure 2: Engraftment of Lin− cells into developing mouse retina.
Figure 3: Lin− HSC and GFAP-expressing astrocytes localize to sites of retinal injury.
Figure 4: Lin− cells rescue the vasculature of the retinal degeneration mouse.
Figure 5: Lin− HSC integrate into, and maintain, retinal vasculature in rd/rd mice.
Figure 6: T2-TrpRS-transfected Lin− cells inhibit the development of mouse retinal vasculature.

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Acknowledgements

We thank the TSRI FACS Facility; E. Aguilar and R. Gariano for assistance with the laser-induced retinal injury model; S. Fallon, M. Ritter, M. Dorrell and G. Nemerow for helpful suggestions and J. Isner for insightful discussions. This work was supported by the National Eye Institute (EY11254 and EY12599 to M.F.), a Core Grant for Vision Research (EY 12598), the National Cancer Institute (CA92577 to P.S.), the Robert Mealey Program for the Study of Macular Degenerations (to M.F.), and the National Foundation for Cancer Research (P.S.).

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Authors and Affiliations

  1. Department of Cell Biology, The Scripps Research Institute, La Jolla, California, USA

    Atsushi Otani, Karen Kinder & Martin Friedlander

  2. Department of Molecular Biology and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA

    Karla Ewalt, Francella J. Otero & Paul Schimmel

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  1. Atsushi Otani
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Correspondence to Martin Friedlander.

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Otani, A., Kinder, K., Ewalt, K. et al. Bone marrow–derived stem cells target retinal astrocytes and can promote or inhibit retinal angiogenesis. Nat Med 8, 1004–1010 (2002). https://doi.org/10.1038/nm744

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