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    • br Ntf mediated effects of stem

    2018-11-06


    Ntf-mediated effects of stem cells
    Ivit/subretinal stem cell implantation The fate of transplanted stem order gap 27 in the eye remains undetermined and thus the incidence of immune rejection, differentiation into unpredicted phenotypes and unbridled migration within CNS neuropil, together with possible oncogenesis, all remain poorly defined. Safeguards against these outcomes include encapsulation of the stem implant (Zhang et al., 2011) and genetic modification so that the cells carry inducible suicide genes, such as viral-derived thymidine kinase allowing selective destruction of the transplanted cells when treated with the toxic drug ganciclovir (Zhang et al., 2011). However, the potential risks of transplanting stem cells in the eye may have been exaggerated where cell movement is restrained and immune reactions muted. For example, after ivit injection, MSC cluster in the vitreous body (Johnson et al., 2010; Haddad-Mashadrizeh et al., 2013; Mead et al., 2013, 2013), although a small number do migrate into the retina they are neither tumorigenic nor exhibit uncontrolled growth (Johnson et al., 2010; Mendel et al., 2013; Tzameret et al., 2014). In laser-induced glaucoma and retinal injury, ivit BMSCs also migrate into the retina (Singh et al., 2012) where they continue to proliferate (Wang et al., 2010). After subretinal transplantation, NSCs remain immature for at least 7months, barely proliferate and neither exhibit uncontrolled growth nor oncogenesis, but they do migrate from the injection site within the subretinal space (McGill et al., 2012; Lu et al., 2013). By contrast, after ivit transplantation, NSCs either attach to the retina and lens where they remain (Jung et al., 2013), or integrate into the inner retinal layers (Grozdanic et al., 2006). ESC-derived RPE cells transplanted into the subretinal space of Royal College of Surgeon (RCS) rats (which spontaneously undergo RPE and subsequent photoreceptor degeneration) survive for over 200days, preserve visual function with evidence of neither teratoma formation (Lu et al., 2009) nor proliferation (Vugler et al., 2008). Reactive retinal gliosis rather than penetration of the internal limiting membrane is proposed as a major limitation to retinal integration of ESC after ivit implantation (Banin et al., 2006); whilst after subretinal grafting cell migration is more extensive (Banin et al., 2006; Lamba et al., 2009) yet still hindered by the outer limiting membrane (West et al., 2008).
    Immunological acceptance of stem cells transplanted into the eye The vitreous cavity, like the anterior chamber of the eye, is an immunoprivileged environment (Jiang and Streilein, 1991) and thus amenable to cell transplantation. MSC fail to trigger an immune response when challenged with allogeneic lymphocytes and MSC-derived factors inhibit the proliferation of immunological cells (Kode et al., 2009; Singer and Caplan, 2011). These immunosuppressive/immunomodulatory actions of BMSC have led to Phase I (Le Blanc et al., 2004), Phase II (Le Blanc et al., 2008) and Phase III (Martin et al., 2010) clinical trials for the treatment of steroid refractory graft-versus-host disease. ADSCs suppress the immune system with the same efficacy as BMSC in vitro (Puissant et al., 2005) and increase the survival rate of transplants in animal models of graft versus host disease (Yañez et al., 2006), whereas DPSC are as efficient as BMSC in the suppression of T cell proliferation in vitro (Pierdomenico et al., 2005). Thus, the failure of the host to launch immune reactions after ivit/subretinal implantation of MSC is probably explained by both the immune privileged status of these sites and the immunosuppressive properties of MSC. For example, immunosuppression is not required and adverse effects are not recorded after human BMSC (Johnson et al., 2010; Levkovitch-Verbin et al., 2010; Tzameret et al., 2014)/ADSC (Haddad-Mashadrizeh et al., 2013)/rodent DPSC (Mead et al., 2013) transplantation into the eye. Equally, although not immunosuppressive, iPSC derived from the somatic cells of the recipient carry the same histocompatibility antigens and do not require immunosuppression after transplantation. By contrast, ESCs/NSCs require immunosuppression when transplanted into the CNS in animals and, since autologous transplantation is not possible, immunosuppression is required in NSC-based treatment (Cummings et al., 2005; Lu et al., 2012; Schwartz et al., 2012; Lu et al., 2013). Indeed, NSC transplantation into the subretinal space requires daily immunosuppressive treatment with cyclosporine A and dexamethasone (McGill et al., 2012). When transplanted into the vitreous without immunosuppression, NSCs are detected in just 50% of transplanted eyes 32days after grafting (Grozdanic et al., 2006) suggesting that the immunoprivileged environment of the vitreous does not sustain survival of NSC. ESC-derived RPE cells are one of the first ESC based therapies to be used in humans and early reports of subretinal transplantation as a treatment for AMD confirm their safety, although patients require immunosuppression throughout (Schwartz et al., 2012).