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  • In this report we established mouse models suitable


    In this report, we established mouse models suitable for human retinal cell transplantation by introducing phosphodiesterase 6B (Pde6b) mutant allele from retinal degeneration (rd) mouse models into NOG background. Pde6b (rd1) and Pde6b (rd10) mice are well-studied and frequently used animal models of retinal degeneration with different degeneration speeds. The missense point mutation in Pde6b carried in these mice is also found as a causal gene of human autosomal recessive retinitis pigmentosa (RP). Rd1 presents a phenotype of progressive retinal degeneration similar to that seen in C3H and Pde6b (rd1-2J) mice, with the onset of photoreceptor degeneration at around postnatal day 16 (P16), and loss of photoreceptors within the first 3–4 postnatal weeks (Chang et al., 2007, Kim et al., 2008). Rd10 exhibits a slightly slower photoreceptor degeneration starting between P16 and P20, and most of the photoreceptors disappear by P60 (Pennesi et al., 2012). We first characterized the degeneration phenotype in these rd mice with NOG background because immune responses Phos-tag Biotin have been suggested to accompany or modulate the pathogenesis of neurodegenerative diseases (Cuenca et al., 2014, González et al., 2014, Jin et al., 2016, Noailles et al., 2016, Yoshida et al., 2013a, Yoshida et al., 2013b, Zabel et al., 2016, Zeng et al., 2005, Zhao et al., 2015). Rd1 mice in the background of SCID, or in combination with RAG-1 knockout (no functional B and T cells) or a C1qα knockout (no functional classical complement activation pathway) (Rohrer et al., 2007) or NOD (no functional B and T cells and low activity of NK cells) (Mishra et al., 2017) showed no difference in the degeneration speed, while rd10 mice with Ccr2 knockout (Guo et al., 2012) and Cx3cr1 knockout (Peng et al., 2014) exhibited slower degeneration. We next transplanted hESC retinal sheets, to confirm the long-term survival and functional integration of graft Phos-tag Biotin in NOG-rd1-2J mice by immunohistochemistry and electrophysiology recording.
    Discussion In this study, we established two immunodeficient retinal degeneration model mouse strains, NOG-rd1-2J and NOG-rd10, for transplantation of human retinal cells or tissue. Initially, our goal was to obtain two model lines with different degeneration speeds. However, degeneration was unexpectedly fast in NOG-rd10 mice in comparison with rd10 mice. In these NOG backgrounds, immune cells such as T cells, B cells, and NK cells were markedly reduced, whereas microglia were similarly present compared with non-NOG mice. We did not observe infiltration of these T, B, or NK cells in the retina during the photoreceptor degeneration in either rd1-2J or rd10 mice, even though these mouse lines both possess an intact immune system. There are controversial reports about the role of microglia in retinal degeneration (Arroba et al., 2011, Jin et al., 2016, Peng et al., 2014). We observed microglia infiltration into ONL after the detection of initial apoptosis marker appearance in photoreceptor cells, both in NOG-rd10 and rd10 mice. Although some reported that T cells could influence microglia to be neurotoxic or neurotrophic (González et al., 2014), the lack of T cell infiltration argues against this mechanism. The pro-inflammatory phenotype of microglia indicated by CD68 staining was similarly observed in both rd10 and NOG-rd10 mice. It was reported that different inbred strains showed markedly different sensitivities to light (LaVail et al., 1987). Since retinas from dark-reared rd10 mice exhibited delayed degeneration onset while dark rearing had no effect on rd1-2J retinal degeneration (Chang et al., 2007), sensitivity to light may affect the pathology of rd10 mice. In our study, since degeneration in both rd10 and NOG-rd10 mice was slowed down when dark-reared, in addition to light effect, the immunodeficiency or other genetic differences between the different strain backgrounds may have also accelerated the degeneration.