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M. Sasahara, A. Otani, A. Oishi, H. Kojima, Y. Yodoi, H. Nakamura, N. Yoshimura; Bone Marrow-Derived Microglia Control Inherited Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4379.
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© ARVO (1962-2015); The Authors (2016-present)
We have previously demonstrated intravitreally injected Lin- hematopoietic stem cells (HSCs) from bone marrow (BM) rescued inherited retinal degeneration (Otani, et al. 2004 J Clin Invest). In this study, we investigated whether the endogenous BM-derived HSCs in circulation have any roles in the pathogenesis of retinal degeneration.
We generated chimera mice of retinal degeneration (rd1, rd10, rd12) with GFP+ BM using bone marrow transplantation with lethal irradiation, and counted the recruited BM-derived cells in the degenerating retina. Subsequently, we performed immunohistochemistry to determine how the recruited BM-derived cells differentiate. Next, we focused on stromal derived factor-1 (SDF-1), which is known as a retention factor of circulating HSCs to the tissue, and investigated how the homing of circulating HSCs to the retina was changed by inhibition of SDF-1 and how did the inhibitory effects contribute to the retinal degeneration. In addition, we performed systemic depletion of myeloid progenitors using clodronate liposome (CL-lip) to investigate the role of BM-derived cells.
We found that in contrast to the control strain, vast GFP+ cells were recruited into the retina with the progression of retinal degeneration in three different mouse models. Immunohistochemistry revealed that most of the cells recruited were positive for microglia markers (Iba-1+, F4/80+, CD11b+) with three different morphologies; spindle-like cells along the degenerating retinal vessels, amoeboid-amorphous cells, and ramified-dendritic cells. Only few CD31+GFP+ tube-like cell were infiltrated into microvasculature. These cells were not stained by GFAP, alpha-smooth muscle actin, or neu-N. Some of these microglia migrated toward the photoreceptor layer and subretinal spaces with expression of CD68. Real-time PCR analysis showed SDF-1 was up-regulated in the degenerating retina. In anti-SDF-1 injected eyes, GFP+ cells were significantly reduced compared to saline injected eyes (P=0.01) and exhibited accelerated vascular and neural degenerations. In addition, systemic depletion of myeloid progenitors also accelerated the degenerative process.
Our data suggest that circulating HSCs are recruited to the sites of retinal degeneration and differentiate into microglial cells. These BM-derived cells may have a protective role in the neural and vascular degeneration and may control the speed of inherited retinal degeneration.
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