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Survival and functionality of xeno‐free human embryonic stem cell–derived retinal pigment epithelial cells on polyester substrate after transplantation in rabbits

: Ilmarinen, T.; Thieltges, F.; Hongisto, H.; Juuti-Uusitalo, K.; Koistinen, A.; Kaarniranta, K.; Brinken, R.; Braun, N.; Holz, F.G.; Skottman, H.; Stanzel, B.V.


Acta Ophthalmologica 97 (2019), No.5, pp.E688-E699
ISSN: 1755-375X
ISSN: 1755-3768
Journal Article
Fraunhofer IBMT ()

Purpose To study immunogenic properties of human embryonic stem cell-derived retinal pigment epithelium (hESC-RPE) and to evaluate subretinal xenotransplantation of hESC-RPE on porous polyethylene terephthalate (PET) in rabbits. Methods Human ESC-RPE cells were characterized by morphology, transepithelial electrical resistance (TER), protein expression and photoreceptor outer segment phagocytosis in vitro. Expression of major histocompatibility complex (MHC) proteins was assessed in conventionally or xeno-free produced hESC-RPE +/- interferon-gamma (IFN-gamma) stimulation (n = 1). Xeno-free hESC-RPE on PET with TER or PET alone were transplanted into 18 rabbits with short-term triamcinolone +/- extended tacrolimus immunosuppression. Rabbits were monitored by spectral domain optical coherence tomography. After 4 weeks, the eyes were processed for histology and transmission electron microscopy. Results Upon in vitro IFN-gamma stimulation, xeno-free hESC-RPE expressed lower level of MHC-II proteins compared to the conventional cells. Outer nuclear layer (ONL) atrophy was observed over the graft in most cases 4 weeks post-transplantation. In 3/4 animals with high TER hESC-RPE, but only in 1/3 animals with low TER hESC-RPE, ONL atrophy was observed already within 1 week. Retinal cell infiltrations were more frequent in animals with high TER hESC-RPE. However, the difference was not statistically significant. In three animals, preservation of ONL was observed. Weekly intravitreal tacrolimus did not affect ONL preservation. In all animals, hESC-RPE cells survived for 4 weeks, but without tacrolimus, enlarged vacuoles accumulated in hESC-RPE (n = 1). Conclusions Xenografted xeno-free hESC-RPE monolayers can survive and retain some functionality for 4 weeks following short-term immunosuppression. The preliminary findings of this study suggest that further investigations to improve transplantation success of hESC-RPE xenografts in rabbits should be addressed especially toward the roles of hESC-RPE maturation stage and extended intravitreal immunosuppression.