Project Leader
(Apr. 2018—Jul. 2019)
Masayo Takahashi M.D., Ph.D.
(Aug. 2019—Mar. 2022)
Eisuke Nishida Ph.D.

Laboratory for Retinal Regeneration

[Closed Mar. 2022]

The retina has been called the "approachable part of the brain," owing to its relatively simple structure and its location near the body surface, and for these reasons it serves as a useful and experimentally amenable model of the central nervous system. Until very recently, it was thought that in adult mammals the retina was entirely incapable of regenerating, but we now know that at least new retinal neurons can be generated after being damaged. This has opened up new hope that the adult retina may retain the ability to regenerate neurons and even to reconstitute the neural network. We are now exploring the exciting prospect that, by transplanting cells from outside of the retina or by regeneration from intrinsic progenitor cells, it may one day be possible to restore lost function to damaged retinas.

Our research into retinal regeneration seeks to achieve clinical applications by developing methods for inducing stem cells or embryonic stem cells to differentiate into retinal neurons and pigment epithelial cells in sufficient quantities for use in the treatment of patients suffering from conditions in which such cells have been damaged or lost. We must also ensure that such cells establish viable grafts upon transplantation and induce the reconstitution of functional neural networks. We also hope to develop means of promoting true regeneration by activating endogenous stem cells to replace cells lost to trauma or disease and thus repair damaged tissues. Access to a broad spectrum of developmental biological research information will be key to the achievement of these goals, and we appreciate the opportunities for exchange that working in the environment provided by the RIKEN BDR.

Therapeutic applications cannot be developed from basic research alone; the clinical approach - a thorough understanding of the medical condition to be treated is equally important. For conditions such as retinitis pigmentosa, even the successful transplantation of cells in animal models may not necessarily be translatable to a human clinical therapy without an understanding of the underlying genetics and possible immunological involvement. Our goal is to study retinal regeneration based on both a strong foundation in basic research and solid clinical evidence.

Research Theme

Retinal cell transplantation
Genetic diagnosis of retinitis pigmentosa
Relationship between photoreceptor death and environment in retinitis pigmentosa
Development of regenerative medicine system
iPSC-derived retinal ganglion cell

Selected Publications

Kanda GN, Tsuzuki T, Terada M, et al.
Robotic search for optimal cell culture in regenerative medicine.
eLife 11, e77007 (2022) doi: 10.7554/eLife.77007

Yamasaki S, Tu HY, Matsuyama T, et al.
A Genetic modification that reduces ON-bipolar cells in hESC-derived retinas enhances functional integration after transplantation.
iScience 25(1), 103657 (2022) doi: 10.1016/j.isci.2021.103657

Ochiai K, Motozawa N, Terada M, et al.
A Variable Scheduling Maintenance Culture Platform for Mammalian Cells.
SLAS technology 26(2), 209-217 (2021) doi: 10.1177/2472630320972109

Takahashi TM, Sunagawa GA, Soya S, et al.
A discrete neuronal circuit induces a hibernation-like state in rodents.
Nature 583, 109-114 (2020) doi: 10.1038/s41586-020-2163-6

Matsumoto E, Koide N, Hanzawa H, et al.
Fabricating retinal pigment epithelial cell sheets derived from human induced pluripotent stem cells in an automated closed culture system for regenerative medicine.
PloS one 14(3), e0212369 (2019) doi: 10.1371/journal.pone.0212369

Kime C, Kiyonari H, Ohtsuka S, et al.
Induced 2C Expression and Implantation-Competent Blastocyst-like Cysts from Primed Pluripotent Stem Cells.
Stem Cell Reports 13(3), 485-498 (2019) doi: 10.1016/j.stemcr.2019.07.011

Kitahata S, Tanaka Y, Hori K, et al.
Critical Functionality Effects from Storage Temperature on Human Induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelium Cell Suspensions.
Scientific Reports 9, 2891 (2019) doi: 10.1038/s41598-018-38065-6

Tu HY, Watanabe T, Shirai H, et al.
Medium- to long-term survival and functional examination of human iPSC-derived retinas in rat and primate models of retinal degeneration.
EBioMedicine 39, 562-574 (2019) doi: 10.1016/j.ebiom.2018.11.028

Goto S, Onishi A, Misaki K, et al.
Neural retina-specific Aldh1a1 controls dorsal choroidal vascular development via Sox9 expression in retinal pigment epithelial cells.
eLife 7, e32358 (2018) doi: 10.7554/eLife.32358.001

Iraha S, Tu HY, Yamasaki S, et al.
Establishment of immunodeficient retinal degeneration model mice and functional maturation of human ESC-derived retinal sheets after transplantation.
Stem Cell Reports 10, 1059-1074 (2018) doi: 10.1016/j.stemcr.2018.01.032

Mandai M, Watanabe A, Kurimoto Y, et al.
Autologous induced stem-cell-derived retinal cells for macular degeneration.
The New England Journal of Medicine 376, 1038-1046 (2017) doi: 10.1056/NEJMoa1608368

Mandai M, Fujii M, Hashiguchi T, et al.
iPSC-derived retinal transplants improve vision in rd1 end-stage retinal degeneration mice.
Stem Cell Reports 8, 69-83 (2017) doi: 10.1016/j.stemcr.2016.12.008

Sugita S, Iwasaki Y, Makabe K, et al.
Successful transplantation of retinal pigment epithelial cells from MHC homozygote iPSCs in MHC-matched models.
Stem Cell Reports 7(4), 635-648. (2016) doi: 10.1016/j.stemcr.2016.08.010

Shirai H, Mandai M, Matsushita K, et al.
Transplantation of human embryonic stem cell-derived retinal tissue in two primate models of retinal degeneration.
Proceedings of the National Academy of Sciences of the United States of America 113(1), E81-90 (2016) doi: 10.1073/pnas.1512590113

Kamao H, Mandai M, Okamoto S, et al.
Characterization of human induced pluripotent stem cell-derived retinal pigment epithelium cell sheets aiming for clinical application.
Stem Cell Reports 2, 205-218 (2014) doi: 10.1016/j.stemcr.2013.12.007

Jin ZB, Okamoto S, Osakada F, et al.
Modeling retinal degeneration using patient-specific induced pluripotent stem cells.
PLoS One 6, e17084 (2011) doi: 10.1371/journal.pone.0017084