Preparation of retinal pigment epithelium and retinal organoids from universal human pluripotent stem cells by efficient and xenofree differentiation protocol

Project Details

Description

Macular degeneration (MD), characterized by degeneration of retinal cells, such as retinal pigmental epithelium (RPE) and/or photoreceptor cells, causes severe vision loss in patients. Subretinal transplantation of RPE differentiated from human pluripotent stem cells (hPSCs) including human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs) into patients are a promising stem cell therapy for treatment of AMD (age-related macular degeneration) and Stargardt’s macular dystrophy. If we can prepare universalhiPSCs and universal hiPSC-derived RPE and RPE organoids, which show immune tolerance when the cells are contacted with allogenic immune cells such as natural killer (NK) cells, macrophages and cytotoxic CD8+ cells, we will have off-the-shelf universal hiPSC-derived RPE and RPE organoids, which can be used for the treatment of any patients of AMD and Stargardt’s macular dystrophy without use of immunosuppressive medicine. Weuse universal hiPSCs, which were originally developed without gene editing by our group, 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 were prepared by mixing amniotic fluids obtained from multi donorswhere no immune rejection of the stem cells (universal amniotic fluid stem cells) can be survived during the mixing of allogenic amniotic fluids from multi donors, 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) and RPEorganoids using several inhibitors to speed up their differentiation. We will develop efficient and optimal differentiation protocol and optimal cell culture materials for differentiation of universal hiPSCs into RPE and RPE organoids with high efficiency and high purity. Universal hiPSCs and universal hiPSC-derived RPE and RPE organoids will be delivered to Dr Chou’s group (Sub project 2) and they will characterize universal hiPSCs and transplant universal hiPSC-derived RPE and RPE organoids into Royal College of Surgeons (RCS) ratsand nude rats subretinally, where RCS rats are an animal model of dry AMD disease. We will evaluate immune response of RPE and RPE organoids derived from universal hiPSCs as well as conventional hiPSCs and hESCs using allogenic mononuclear cells containing NK cells, macrophages and cytotoxic CD8+ cells. From collaboration with Dr Chou’s group (Sub project 2), We will find the effect of universal hiPSC-derived RPE and RPE organoids from pigmentation (RPE survival) on rats’ eyes compared to conventional hESC-derived RPE. We will discuss advantages of usage of universal hiPSC-derived RPE and RPE organoids transplantation in the animal model of dry AMD disease for future clinical application of transplantation of universal hiPSC-derived RPE into patients with AMD and Stargardt’s macular dystrophy. Our final goal of this project is to develop off-the-shelf universal hiPSC-derived RPE and RPE organoids for treatment of any patients with AMD and Stargardt’s macular dystrophy without usage of immunosuppressive medicine.
StatusActive
Effective start/end date1/01/2431/12/24

UN Sustainable Development Goals

In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This project contributes towards the following SDG(s):

  • SDG 3 - Good Health and Well-being
  • SDG 5 - Gender Equality
  • SDG 17 - Partnerships for the Goals

Keywords

  • Universal human induced pluripotent stem cells
  • Age-related macular degeneration
  • Amniotic fluid stem cell
  • Retinal pigment epithelium
  • Organoids
  • Human leukocyte antigen
  • Immune tolerance

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