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  • br Introduction Cell transplantation therapies using embryon

    2021-07-21


    Introduction Cell transplantation therapies using embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC)-derived retinal tissue (ESC/iPSC retina) or octanoic acid have emerged as therapeutic options for retinal degeneration following recent breakthroughs. A number of groups have shown that transplantation of postnatal or ESC/iPSC-derived photoreceptor precursor cells can integrate and restore visual function after transplantation into an adult mouse model of retinal degeneration that retains the photoreceptor layer (outer nuclear layer [ONL]) (Lamba et al., 2009, Pearson et al., 2012, Tucker et al., 2011), although the mechanism by which photoreceptor function is restored has recently been suggested as rescue of surviving host cells by material transfer from donor cells, rather than by direct cell integration (Pearson et al., 2016, Santos-Ferreira et al., 2016a, Singh et al., 2016). Another breakthrough was the introduction of a protocol for self-organizing three-dimensional retinal differentiation from mouse ESCs (mESCs) (Eiraku et al., 2011), which was successfully adapted to human ESCs (hESCs) (Nakano et al., 2012) and human iPSCs (hiPSCs) (Zhong et al., 2014). Since then, in addition to the increasing number of reports that mouse or hESC/iPSC-derived photoreceptor precursors could integrate into, or transfer materials to, host ONL (Decembrini et al., 2014, Gonzalez-Cordero et al., 2013, Hambright et al., 2012, Santos-Ferreira et al., 2016b, Zhu et al., 2017), we and others have reported that transplanted ESC/iPSC retinal sheets or photoreceptors can make de novo synaptic connections and restore some visual functions in end-stage retinal degeneration models with no ONL structure (Assawachananont et al., 2014, Barnea-Cramer et al., 2016, Mandai et al., 2017, Shirai et al., 2015). Human ESCs take as long as 200 days to differentiate into fully mature retina, which was presented by immunohistology in monkeys and also by the presence of outer segments in nude rats following the transplantation (Shirai et al., 2015). However, hESC retinal cells do not always mature properly in xenograft rodent models, especially when there is damage due to the surgical procedure (Hambright et al., 2012). Although some researchers reported successful transplantation of human cells in rodent hosts with immunosuppression, graft survival was usually monitored for a relatively short period such as within several weeks (Barnea-Cramer et al., 2016). Even with immunosuppression, mild rejection can be observed that may inhibit synaptic formation (Larsson et al., 2000). For these reasons, SD-Foxn1 Tg(S334ter)3LavRrrc rats were developed (Seiler et al., 2014, Seiler et al., 2017), and we reported that transplanted hESC retina developed an organized ONL with potential synaptic connections to host bipolar cells (Shirai et al., 2015). Although the SD-Foxn1 Tg(S334ter)3LavRrrc rat is a good model for proof-of-concept studies using human cells, mouse models for which abundant phenotypic studies and gene expression databases are available would be more desirable. Moreover, mice are more accessible to genetic manipulations such as introduction of reporter genes. Recently, Zhu et al. (2017) reported up to 9 months’ survival of transplanted hESC-derived photoreceptors with some function in IL2Rg-deficient CRX-mutant mice, but the possibility of material transfer cannot be excluded due to the remaining host photoreceptors. Thus, immunodeficient end-stage retinal degeneration mouse models with absent ONL structure would be useful for preclinical studies featuring transplantation of hESC/iPSC-derived cells and tissues. In 2002, Ito et al. (2002) established an appropriate animal recipient model for xenotransplantation: non-obese diabetes (NOD)/Shi-SCID, IL2Rgnull (NOG) mice. octanoic acid Characteristics of NOG mice are as follows: (1) lack of T, B, and natural killer (NK) cells; (2) reduced function of macrophage and dendritic cells; and (3) lack of complement activity. This NOG mouse model has been used to study the human lymphoid system by transplanting human cord blood-derived hematopoietic stem cells, and is very useful for testing the tumorigenicity of human cells (Kanemura et al., 2014, Machida et al., 2009, Watanabe et al., 2011).