Generation and differentiation of universal human pluripotent stem cells into retinal pigment epithelium

Project Details


Stem cell therapy, especially subretinal transplantation of RPE (retinal pigment epithelium) differentiated from human pluripotent stem cells (hPSCs) including hESCs and hiPSCs into patients are a promising method for treatment of dry AMD (age-related macular degeneration) and Stargardt’s macular dystrophy. If we can prepare universal hiPSCs and universal hiPSC-derived RPE, which do not show immunoresponsive when the cells arecontacted with allogenic immune cells such as cytotoxic CD8+ cells, natural killer (NK) cells and macrophages, we can produce off-the-shelf universal hiPSC-derived RPE, which can be used for the treatment of any patients of dry AMD and Stargardt’s macular dystrophy without use of immunosuppressive medicine. We will develop universal hiPSCs without gene editing, which do not show human leukocyte antigen (HLA) class I and class II where universal hiPSCs and their differentiated cells do not show immune rejection when these cells are transplanted into any patients having different HLA class I and class II types. Our innovative universal hiPSCs are prepared by mixing amniotic fluids obtained from multi donors where no immune rejection of the stem cells (universal amniotic fluid stemcells) can be survived during the mixing of allogenic amniotic fluids from multi donors (Key technology of this project, under submission into US patent (A. Higuchi), and preliminary data publication in Cell Prolif, 54 (2021) e12995) (A. Higuchi et al.)), whereas conventional universal hiPSCs are prepared using gene editing such as Crispr/Cas9 technology, which are difficult to be approved in clinical application because of their gene editing. Universal hiPSCs are differentiated into retinal pigment epithelium (RPE) using several inhibitors to speed up their differentiation. We will develop optimal differentiation protocol and optimal cell culture materials for differentiation of universal hiPSCs into RPE with high efficiency and high purity. Universal hiPSCs and universal hiPSC-derived RPE will be delivered to Dr Chou’s group (Sub project 2) and they will characterize universal hiPSCs and transplant universal hiPSC-derived RPE into Royal College of Surgeons (RCS) rats and nude rats subretinally, which are an animal model ofdry AMD disease. From collaboration with Dr Chou’s group (Sub project 2), We will find the effect of universal hiPSC-derived RPE from pigmentation (RPE survival) on rats’ eyes compared to conventional hESC(H9)-derived RPE. We will discuss advantages of usage of universal hiPSC-derived RPE transplantation in the animal model of dry AMD disease for future clinical application of transplantation of universal hiPSC-derived RPE into patientswith dry AMD and Stargardt’s macular dystrophy. Our final goal of this project is to develop off-the-shelf universal hiPSC-derived RPE for treatment of any patients with dry AMD and Stargardt’s macular dystrophy without usage of immunosuppressive medicine.
Effective start/end date1/01/2231/12/22


  • Universal human induced pluripotent stem cells
  • age-related macular degeneration
  • amniotic fluid stem cell
  • retinal pigment epithelium
  • human leukocyte antigen
  • immune tolerance


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