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A. Otani, S. Hanekamp, M.I. Dorrell, M. Friedlander; Adult Bone Marrow-derived Endothelial Progenitor Cells Exhibit Neurotrophic Rescue Effect in rd/rd Mice . Invest. Ophthalmol. Vis. Sci. 2003;44(13):1016.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: We have recently shown (Nature Medicine 8:1004) that intravitreally injected Lin- cells derived from adult mouse bone marrow (BM) contain a population of endothelial progenitor cells (EPC) that can utilize a retinal astrocytic template and participate in the formation of patent retinal blood vessels. In this study we evaluate the neurotrophic effect of these cells in the rd/rd mouse after intravitreal injection. Methods: MACS was used to separate Lin- endothelial progenitor cells from bone marrow of enhanced green fluorescent protein (eGFP), C3H (rd/rd), FVB (rd/rd) mice. Cells were injected intravitreally into P6 C3H or FVB mouse eyes and retinas collected at various time points. The vasculature was analyzed in the scanning laser confocal microscope after staining with antibodies to CD31 and retinal histology after nuclear staining with DAPI. Microarray gene expression analysis of mRNA from retinas at varying time points was also used to identify genes potentially involved in the effect. Results: Eyes of rd/rd mice had profound degeneration of both neurosensory retina and retinal vasculature by P21. Eyes of rd/rd mice treated with Lin- cells on P6 maintained a normal retinal vasculature for as long as 6 months; both deep and intermediate layers were significantly improved when compared to the controls at all timepoints (1M, 2M, and 6M). In addition, we observed that retinas treated with Lin- cells were also thicker (1M; 1.2-fold, 2M; 1.3-fold, 6M; 1.4-fold) and had greater numbers of cells in the outer nuclear layer (1M; 2.2-fold, 2M; 3.7-fold, 6M; 5.7-fold). Large scale genomic analysis of "rescued" (e.g., Lin- HSC) compared to control (untreated or non-Lin- treated) rd/rd retinas demonstrated a significant up-regulation of genes encoding sHSPs (small heat shock proteins) and specific growth factors that correlated with vascular and neural rescue. Conclusions: BM-derived EPCs significantly and reproducibly induce maintenance of a normal vasculature and dramatically increased photoreceptor and other neuronal cell layers in the rd/rd mouse. This neurotrophic rescue effect is correlated with significant up regulation of small heat shock proteins and certain growth factors and, thus, may provide insights into possible therapeutic approaches to currently untreatable retinal degenerative disorders.
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