Michiko Mandai

Kobe City Eye Hospital　Research Center

Purpose: Retinitis pigmentosa represents a leading cause of blindness in developed countries, yet effective treatments for the disease remain unestablished. Previous studies have demonstrated the potential of stem cell-derived retinal organoid (SC-RO) sheet transplantation to form host-graft synapses and to improve light responsiveness in animal m...

The retinal fovea in human and nonhuman primates is essential for high acuity and color vision. Within the fovea lies specialized circuitry in which signals from a single cone photoreceptor are largely conveyed to one ON and one OFF type midget bipolar cell (MBC), which in turn connect to a single ON or OFF midget ganglion cell (MGC), respectively....

This study evaluates the transplantation of induced pluripotent stem cell (iPSC)-derived retinal organoids into patients with advanced retinitis pigmentosa using adaptive optics optical coherence tomography (AO-OCT) to monitor retinal changes over two years post transplantation. Our results confirmed successful engraftment and increased retinal thi...

Clinical studies using suspensions or sheets of human pluripotent cell-derived retinal pigment epithelial cells (hiPSC-RPE) have been conducted globally for diseases such as age-related macular degeneration. Despite being minimally invasive, cell suspension transplantation faces challenges in targeted cell delivery and frequent cell leakage. Conver...

Purpose We aimed to explore the potential benefits of retinal pigment epithelium (RPE) replacement therapy in patients with Bietti crystalline dystrophy (BCD) by assessing the disease pathology with the distinctive relationship between fundus autofluorescence (FAF) abnormality and visual field defect (VFD). Methods Sixteen eyes from 16 patients wi...

This study aimed to investigate how the extent and central/peripheral location of the residual visual field (VF) in patients with late-stage inherited retinal diseases (IRDs) are related to retinal sensitivity detected using full-field stimulus testing (FST). We reviewed the results of Goldmann perimetry and FST from the medical records of patients...

Pluripotent stem cell-based therapy for retinal degenerative diseases is a promising approach to restoring visual function. A clinical study using retinal organoid (RO) sheets was recently conducted in patients with retinitis pigmentosa. However, the graft preparation currently requires advanced skills to identify and excise suitable segments from...

Among the genome-editing methods for repairing disease-causing mutations resulting in dominant inhibition, homology-independent targeted integration (HITI)-mediated gene insertion of the normal form of the causative gene is useful because it allows the development of mutation-agnostic therapeutic products. For the rapid optimization and validation...

Purpose Novel therapeutic options, such as regenerative medicine and gene therapy, are now emerging as viable treatment options for patients with severe visual impairments, such as retinitis pigmentosa (RP). Gradable assessment of patients’ visual function is essential to consider treatment options and to evaluate treatment outcomes; however, evalu...

In recent decades, many researchers have attempted to restore vision via transplantation of retina/retinal cells in eyes with retinal degeneration. The advent of induced pluripotent stem cells (iPSC) and retinal organoid induction technologies has boosted research on retinal regeneration therapy. Although the recognition of functional integration o...

Three-dimensional retinal organoids (3D-retinas) are a promising graft source for transplantation therapy. We previously developed self-organizing culture for 3D-retina generation from human pluripotent stem cells (hPSCs). Here we present a quality control method and preclinical studies for tissue-sheet transplantation. Self-organizing hPSCs differ...

We report the generation and analysis of single-cell RNA-Seq data (> 38,000 cells) from mouse native retinae and induced pluripotent stem cell (iPSC)-derived retinal organoids at four matched stages of development spanning the emergence of the major retinal cell types. We combine information from temporal sampling, visualization of 3D UMAP manifold...

The discovery of induced Pluripotent Stem) (iPS) cells has instigated innovation in various fields, including ophthalmology. Cell therapy has shown tremendous progress in translational research on retinal diseases, including the first-in-human transplantation of autologous iPS cell-derived retinal pigment epithelium (RPE) cells for patients with ag...

Transplantation of embryonic/induced pluripotent stem cell-derived retina (ESC/iPSC-retina) restores host retinal ganglion cell light responses in end-stage retinal degeneration models with host-graft synapse formation. We studied the immunological features of iPSC-retina transplantation using major histocompatibility complex (MHC)-homozygote monke...

Purpose Novel therapeutic options, such as regenerative medicine and gene therapy are now emerging as viable treatment options for patients with severe visual impairments, such as retinitis pigmentosa (RP). Gradable assessment of patients′ visual function is essential to consider treatment options and to evaluate treatment outcomes, however, evalua...

This study aimed to evaluate the distribution of retinal pigment epithelium (RPE) melanin in patients with retinitis pigmentosa (RP) using entropy measurements by custom-made polarization-sensitive optical coherence tomography (PS-OCT) images, and compare entropy with the intensity of short-wavelength (SW) and near-infrared (NIR) autofluorescence (...

Cell therapy using induced pluripotent stem cell (iPSC) derivatives may result in abnormal tissue generation because the cells undergo numerous cycles of mitosis before clinical application, potentially increasing the accumulation of genetic abnormalities. Therefore, genetic tests may predict abnormal tissue formation after transplantation. Here, w...

Stem cell-based therapy for retinal degeneration is transitioning from the research stage to the clinical stage and is being developed as a treatment across the globe. In clinical studies on induced pluripotent stem cell (iPSC)-derived retinal pigment epithelium (RPE) transplantation, the safety of the technique has started to clarify, and clinical...

Background The BMP signaling pathway plays a key role in growth, differentiation and patterning during neural development. Recent work on the generation of a self-organization of three-dimensional retinal organoid (3D-retina) from human pluripotent stem cells (hPSCs) revealed that addition of recombinant human BMP4 (rhBMP4) promotes retinal differe...

Three-dimensional retinal organoids (3D-retinas) are a promising graft source for transplantation therapy. We previously developed self-organizing culture for 3D-retina generation from human pluripotent stem cells (hPSCs). Here we present a quality control method and preclinical studies for tissue-sheet transplantation. Self-organizing hPSCs differ...

The retinal pigment epithelium (RPE) is essential for the survival and function of retinal photoreceptor cells. RPE dysfunction causes various retinal diseases including age-related macular degeneration (AMD). Clinical studies on ES/iPS cell-derived RPE transplantation for RPE dysfunction-triggered diseases are currently underway. Quantification of...

Regenerative medicine relies on basic research outcomes that are only practical when cost effective. The human eyeball requires the retinal pigment epithelium (RPE) to interface the neural retina and the choroid at large. Millions of people suffer from age-related macular degeneration (AMD), a blinding multifactor genetic disease among RPE degradat...

Pluripotent stem cell (PSC) derived retinal sheet transplanted in vivo can form structured photoreceptor layers, contact with host bipolar cells, and transmit light signals to host retinas. However, a major concern is the presence of graft bipolar cells that may impede host-graft interaction. In this study, we used human ESC-retinas with the deleti...

Several clinical studies have been conducted into the practicality and safety of regenerative therapy using hESC/iPSC-retinal pigment epithelium (RPE) as a treatment for the diseases including age-related macular degeneration. These studies used either suspensions of RPE cells or an RPE cell sheet. The cells can be injected using a minimally invasi...

Purpose: Retinal ganglion cell (RGC) transplantation is a therapeutic approach to replace irreversibly degenerated RGCs in diseases such as glaucoma. However, the application of primary RGCs is limited by the availability of tissues. The goal of this study was to evaluate whether transplanted mouse embryonic stem cell (mESC)-derived RGCs can integ...

ES/iPS-retinal sheet transplantation, which supplies photoreceptors as well as other retinal cells, has been shown able to restore visual function in mice with end-stage retinal degeneration. Here, by introducing a novel type of genetically engineered mouse ES/iPS-retinal sheet with reduced numbers of secondary retinal neurons but intact photorecep...

Currently, retinal pigment epithelium (RPE) transplantation includes sheet and single-cell transplantation, the latter of which includes cell death and may be highly immunogenic, and there are some issues to be improved in single-cell transplantation. Y-27632 is an inhibitor of Rho-associated protein kinase (ROCK), the downstream kinase of Rho. We...

ESC- and iPSC-derived retinal transplantation is a promising therapeutic approach for disease with end-stage retinal degeneration, such as retinitis pigmentosa and age-related macular degeneration. We previously showed medium- to long-term survival, maturation, and light response of transplanted human ESC- and iPSC-retina in mouse, rat, and monkey...

Retinal pigment epithelial (RPE) cells have several functions, including support of the neural retina and choroid in the eye and immunosuppression. Cultured human RPE cells directly suppress inflammatory immune cells. For instance, they directly suppress the activation of T cells in vitro. In contrast, transplanted allogeneic human RPE cells are re...

ES/iPS-retinal sheet transplantation, which supplies photoreceptors as well as other retinal cells, has been shown able to restore visual function in mice with end-stage retinal degeneration. Here, by introducing a novel type of genetically engineered ES/iPS-retinal sheet with reduced numbers of secondary retinal neurons but intact photoreceptor ce...

Various advances have been made to treat retinal diseases, including new treatment strategies and innovations in surgical devices. However, treatment of degenerative retinal diseases, such as retinitis pigmentosa (RP) and age‐related macular degeneration (AMD), continues to pose a significant challenge. In this review, we focus on the use of embryo...

Imaging of melanin in the eye is important as the melanin is structurally associated with some ocular diseases, such as age-related macular degeneration. Although optical coherence tomography (OCT) cannot distinguish tissues containing the melanin from other tissues intrinsically, polarization-sensitive OCT (PS-OCT) can detect the melanin through s...

In patients with retinitis pigmentosa (RP), color fundus photography and fundus autofluorescence (FAF) have been used to estimate the disease progression. To understand the origin and the diagnostic interpretation of the fundus color and FAF, we performed in vivo imaging of fundus color and FAF together with histological analyses of the retinal deg...

Transplantation of retinal pigment epithelial (RPE) sheets derived from human induced pluripotent cells (hiPSC) is a promising cell therapy for RPE degeneration, such as in age-related macular degeneration. Current RPE replacement therapies, however, face major challenges. They require a tedious manual process of selecting differentiated RPE from h...

Regenerative medicine relies on basic research to find safe and useful outcomes that are only practical when cost-effective. The human eyeball requires the retinal pigment epithelium (RPE) for support and maintenance that interfaces the neural retina and the choroid at large. Nearly 200 million people suffer from age-related macular degeneration (A...

Immune attacks are key issues for cell transplantation. To assess the safety and the immune reactions after iPS cells-derived retinal pigment epithelium (iPS-RPE) transplantation, we transplanted HLA homozygote iPS-RPE cells established at an iPS bank in HLA-matched patients with exudative age-related macular degeneration. In addition, local steroi...

Transplantation of autologous human induced pluripotent stem cell-derived retinal pigment epithelial (hiPSC-RPE) sheets is a promising therapy for age-related macular degeneration (AMD). As melanin content is a representative feature of healthy RPE, we used polarization-sensitive optical coherence tomography (PS-OCT) to estimate the relative melani...

We report the generation and analysis of single-cell RNA-Seq data (> 38,000 cells) from native and iPSC-derived murine retina at four matched developmental stages spanning the emergence of the major retinal cell types. We combine information from temporal sampling, visualization of 3D UMAP manifolds, pseudo-time and RNA velocity analyses, to show t...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Retinitis pigmentosa (RP) is a group of hereditary diseases that involve loss of photoreceptors. There has been no established treatment for RP, and it is now the 2nd leading cause of blindness in Japan. Previous clinical researches using human fetal retina transplantation suggested some functional recovery in vision, but it did not become a standa...

A three-dimensional retinal tissue (3D-retina) is a promising graft source for retinal transplantation therapy. We previously demonstrated that embryonic stem cells (ESCs) can generate 3D-retina in vitro using a self-organizing stem cell culture technique known as SFEBq. Here we show an optimized culture method for 3D-retina generation from feeder-...

Given the importance of visual information to many daily activities, retinal degenerative diseases—which include both inherited conditions (such as retinitis pigmentosa) and acquired conditions (such as age-related macular degeneration)—can have a dramatic impact on human lives. The therapeutic options for these diseases remain limited. Since the d...

Introduction The use of optical coherence tomography (OCT) images is increasing in the medical treatment of age-related macular degeneration (AMD), and thus, the amount of data requiring analysis is increasing. Advances in machine-learning techniques may facilitate processing of large amounts of medical image data. Among deep-learning methods, conv...

The objective of this study was to build deep learning models with optical coherence tomography (OCT) images to classify normal and age related macular degeneration (AMD), AMD with fluid, and AMD without any fluid. In this study, 185 normal OCT images from 49 normal subjects, 535 OCT images of AMD with fluid, and 514 OCT mages of AMD without fluid...

Background: We aimed to investigate the deformation of the outer nuclear layer using optical coherence tomography in patients with epiretinal membrane (ERM) and its relationship with metamorphopsia. Methods: Thirty-nine eyes from 39 patients with ERM were included in the study. Patients with the subtypes of pseudo macula hole and lamellar hole w...

Background We aimed to investigate the deformation of the outer nuclear layer using optical coherence tomography in patients with epiretinal membrane (ERM) and its relationship with metamorphopsia. Methods Thirty-nine eyes from 39 patients with ERM were included in the study. Patients with the subtypes of pseudo macula hole and lamellar hole were e...

Background We aimed to investigate the deformation of the outer nuclear layer using optical coherence tomography in patients with epiretinal membrane (ERM) and its relationship with metamorphopsia. Methods Thirty-nine eyes from 39 patients with ERM were included in the study. Patients with the subtypes of pseudo macula hole and lamellar hole were e...

Purpose: To report the results after 4 years of follow-up in a previously presented first case of induced pluripotent stem cell (iPSC)-derived retinal pigment epithelium (RPE) sheet autologous transplantation using multimodal imaging. Design: Follow-up of a single case. Participant: A patient with exudative age-related macular degeneration and...

Background We aimed to investigate the deformation of the outer nuclear layer using optical coherence tomography in patients with epiretinal membrane (ERM) and its relationship with metamorphopsia. Methods Thirty-nine eyes from 39 patients with ERM were included in the study. Patients with the subtypes of pseudo macula hole and lamellar hole were e...

Quantitative and qualitative evaluation of synapses is crucial to understand neural connectivity. This is particularly relevant now, in view of the recent advances in regenerative biology and medicine. There is an urgent need to evaluate synapses to access the extent and functionality of reconstructed neural network. Most of the currently used syna...

describe image processing protocols for DAPI, RIBEYE, and mGluR6 channel, respectively. Immunostaining samples were imaged with a confocal microscope and 5 sequential z-stack images were projected on the z axis, and processed as described in the Figure. After generating ROIs, the following graphical parameters were exported using the “Measure” func...

Estimation of marker density. (A) Relationship between pre-synaptic marker density, post-synaptic marker density and the number of pairs when the maximum distance of pairs is 1 μm. (B) Modified Figure of (A) with the y axis divided by post-synaptic density. (C,B) With different maximum distance of pairs. (D) As distance of pairs increase, the chanc...

Probability density functions of parameters. PDFs were generated by Ideal Synapse and Ideal Noise training data. Likelihoods based on each PDF were used upon estimating the posterior probability of synapse for each synapse candidate. Angle and distance histograms of all the detected synapses are also shown here in the right upper panel. Insets show...

Example of QUANTOS maturity evaluation Sample IHC image of B6J P14 (A) and P21 (C) mouse. On P14, both mature and immature synapses can be found. Scale bar = 10 μm Yellow box area of (A) and (C) were magnified and QUANTOS results are overlaid in (B) and (D) respectively. Upper panels show all synapses detected by QUANTOS with yellow dots, including...

Background: We aimed to investigate the deformation of the outer nuclear layer using optical coherence tomography in patients with epiretinal membrane (ERM) and its relationship with metamorphopsia. Methods: Thirty-nine eyes from 39 patients with ERM were included in the study. Patients with the subtypes of pseudo macula hole and lamellar hole were...

Retinitis Pigmentosa is a group of hereditary diseases with rod photoreceptors degeneration, which is followed by central cone degeneration in the advanced stage. The patients experience night blindness and the progressive loss of visual field. Since the retinal bipolar cells that receive signals from the dying photoreceptors remain for a while, on...

Antibodies used for immunohistochemistry.

Cell replacement therapy is a promising treatment for irreversible retinal cell death in diverse diseases, such as age-related macular degeneration (AMD), Stargardt's disease, retinitis pigmentosa (RP) and glaucoma. These diseases are all characterized by the degeneration of one or two retinal cell types that cannot regenerate spontaneously in huma...

[Background]: We have previously reported that xeno-transplanted human ESC-derived retinas are able to mature in the immunodeficient retinal degeneration rodent models, similar to allo-transplantations using mouse iPSC-derived retina. The photoreceptors in the latter developed outer segments and formed synapses with host bipolar cells, driving ligh...

Background/aim We previously reported that ranibizumab performed better on visual prognosis than photodynamic therapy (PDT) in a Ranibizumab ( L ucentis) A nd P hotodynamic T herapy O n P olypoidal choroidal vasculopathy (LAPTOP) study. To determine if the first-choice treatment, either PDT or intravitreal ranibizumab, has a long-term effect...