Efficient and robust induction of retinal pigment epithelium cells by tankyrase inhibition regardless of the differentiation propensity of human induced pluripotent stem cells.
Transplantation of retinal pigment epithelium (RPE) cells derived from human embryonic stem cells (hESCs) or induced pluripotent stem cells (hiPSCs) hold great promise as a new therapeutic modality for age-related macular degeneration and Stargardt disease. The development of hESC/hiPSC-derived RPE cells as cell-based therapeutic products requires a robust, scalable production for every hiPSC line congruent for patients. However, individual hESC/hiPSC lines show bias in differentiation. Here we report an efficient, robust method that induces RPE cells regardless of the differentiation propensity of the hiPSC lines. Application of the tankyrase inhibitor IWR-1-endo, which potentially inhibits Wnt signaling, promoted retinal differentiation in dissociated hiPSCs under feeder-free, two-dimensional culture conditions. The other tankyrase inhibitor, XAV939, also promoted retinal differentiation. However, Wnt signaling inhibitors, IWP-2 and iCRT3, that target porcupine and β-catenin/TCF, respectively, did not. Further treatment with the GSK3β inhibitor CHIR99021 and FGF receptor inhibitor SU5402 induced hexagonal pigmented cells with phagocytotic ability. Notably, the IWR-1-endo-based differentiation method induced RPE cells even in an hiPSC line that expresses a lower level of the differentiation propensity marker SALL3, which is indicative of resistance to ectoderm differentiation. The present study demonstrated that tankyrase inhibitors cause efficient and robust RPE differentiation, irrespective of the SALL3 expression levels in hiPSC lines. This differentiation method will resolve line-to-line variations of hiPSCs in RPE production and facilitate clinical application and industrialization of RPE cell products for regenerative medicine.
['Ito|Arisa|A|', 'Ye|Ke|K|', 'Onda|Masanari|M|', 'Morimoto|Nao|N|', 'Osakada|Fumitaka|F|']
D002454:Cell Differentiation D017690:Cell Transplantation D002478:Cells, Cultured D006575:Heterocyclic Compounds, 3-Ring D000066449:Human Embryonic Stem Cells D006801:Humans D007094:Imides D057026:Induced Pluripotent Stem Cells D008268:Macular Degeneration D039904:Pluripotent Stem Cells D011804:Quinolines D055213:Retinal Pigment Epithelium D038501:Tankyrases
Retinal pigment epithelium Tankyrase Induced pluripotent stem cells Cell therapy RPE replacement therapy Wnt/β-catenin