Transplantation of Embryonic and Induced Pluripotent Stem Cell-Derived 3D Retinal Sheets into Retinal Degenerative Mice

Assawachananont, Juthaporn; Mandai, Michiko; Okamoto, Satoshi; Yamada, Chikashi; Eiraku, Mototsugu; Yonemura, Shigenobu; Sasai, Yoshiki; Takahashi, Masayo

doi:10.1016/j.stemcr.2014.03.011

Cited by 318 publications

(273 citation statements)

References 34 publications

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“…9). The extracted tissue would likely have to be crumbled during isolation [34], which will reduce tissue's full developmental potential shown by Seiler and Aramant [105]. We demonstrate that larger pieces of hESC-derived retinal tissue, resembling human retinas during weeks 6-12 of development (Supplementary Table S4), could be derived in adherent conditions.…”

Section: Discussionmentioning

confidence: 84%

“…However, the retinal tissue cannot be too differentiated to survive the surgical procedure [33]. In addition, the structural rigidity of retinospheres (cultured in suspension) makes it difficult to isolate a transplantable slice of hESC-derived retina [34]. In this study, we derived immature, long, and flexible 3D retinal tissue from hESCs in adherent conditions.…”

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confidence: 99%

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Characterization of Three-Dimensional Retinal Tissue Derived from Human Embryonic Stem Cells in Adherent Monolayer Cultures

Singh

Mallela

Cornuet

et al. 2015

Stem Cells and Development

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Stem cell-based therapy of retinal degenerative conditions is a promising modality to treat blindness, but requires new strategies to improve the number of functionally integrating cells. Grafting semidifferentiated retinal tissue rather than progenitors allows preservation of tissue structure and connectivity in retinal grafts, mandatory for vision restoration. Using human embryonic stem cells (hESCs), we derived retinal tissue growing in adherent conditions consisting of conjoined neural retina and retinal pigment epithelial (RPE) cells and evaluated cell fate determination and maturation in this tissue. We found that deriving such tissue in adherent conditions robustly induces all eye field genes (RX, PAX6, LHX2, SIX3, SIX6) and produces four layers of pure populations of retinal cells: RPE (expressing NHERF1, EZRIN, RPE65, DCT, TYR, TYRP, MITF, PMEL), early photoreceptors (PRs) (coexpressing CRX and RCVRN), inner nuclear layer neurons (expressing CALB2), and retinal ganglion cells [RGCs, expressing BRN3B and Neurofilament (NF) 200]. Furthermore, we found that retinal progenitors divide at the apical side of the hESC-derived retinal tissue (next to the RPE layer) and then migrate toward the basal side, similar to that found during embryonic retinogenesis. We detected synaptogenesis in hESC-derived retinal tissue, and found neurons containing many synaptophysin-positive boutons within the RGC and PR layers. We also observed long NF200-positive axons projected by RGCs toward the apical side. Whole-cell recordings demonstrated that putative amacrine and/or ganglion cells exhibited electrophysiological responses reminiscent of those in normal retinal neurons. These responses included voltagegated Na + and K + currents, depolarization-induced spiking, and responses to neurotransmitter receptor agonists. Differentiation in adherent conditions allows generation of long and flexible pieces of 3D retinal tissue suitable for isolating transplantable slices of tissue for retinal replacement therapies.

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Section: Discussionmentioning

confidence: 84%

mentioning

confidence: 99%

Characterization of Three-Dimensional Retinal Tissue Derived from Human Embryonic Stem Cells in Adherent Monolayer Cultures

Singh

Mallela

Cornuet

et al. 2015

Stem Cells and Development

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“…Selforganization of hESCs into a cone tissue sheet is reminiscent of the self-formation of hESCs into an optic cup (Nakano et al, 2012). Human cone tissue sheets may be used as a retinal patch for the treatment of macular degenerations, as shown for mouse retinal sheets transplanted into a retinitis pigmentosa mouse model (Assawachananont et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Differentiation of human embryonic stem cells into cone photoreceptors through simultaneous inhibition of BMP, TGFβ and Wnt signaling

et al. 2015

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Cone photoreceptors are required for color discrimination and highresolution central vision and are lost in macular degenerations, cone and cone/rod dystrophies. Cone transplantation could represent a therapeutic solution. However, an abundant source of human cones remains difficult to obtain. Work performed in model organisms suggests that anterior neural cell fate is induced 'by default' if BMP, TGFβ and Wnt activities are blocked, and that photoreceptor genesis operates through an S-cone default pathway. We report here that Coco (Dand5), a member of the Cerberus gene family, is expressed in the developing and adult mouse retina. Upon exposure to recombinant COCO, human embryonic stem cells (hESCs) differentiated into S-cone photoreceptors, developed an inner segment-like protrusion, and could degrade cGMP when exposed to light. Addition of thyroid hormone resulted in a transition from a unique S-cone population toward a mixed M/S-cone population. When cultured at confluence for a prolonged period of time, COCOexposed hESCs spontaneously developed into a cellular sheet composed of polarized cone photoreceptors. COCO showed dosedependent and synergistic activity with IGF1 at blocking BMP/TGFβ/ Wnt signaling, while its cone-inducing activity was blocked in a dosedependent manner by exposure to BMP, TGFβ or Wnt-related proteins. Our work thus provides a unique platform to produce human cones for developmental, biochemical and therapeutic studies and supports the hypothesis that photoreceptor differentiation operates through an S-cone default pathway during human retinal development.

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“…Twentyfour lines were screened to choose the most patient compatible cells. 31 It is now evident that differences in the quality of iPSC clones are largely due to technical variables relating to reprogramming approaches and culture conditions. 4,8,27,32 Additionally, some uncontrolled stochastic events during reprogramming undoubtedly influence gene expression and DNA methylation patterns in even functionally identical iPSC lines.…”

Section: Discussionmentioning

confidence: 99%

“…Recent advances in iPSCs application in disease treatment and discovery of the alternative stem cell-like states during reprogramming 31,35 support the need for efficient and informative approaches to the selection of the best iPSC line in a cohort of functionally similar reprogrammed cells. Screening of dozens of clones that passed the teratoma assay by in vitro differentiation into a required somatic cell line to find the perfect clone for a specific application has not been effective 36,37 and considering the possible need for multiple somatic cell types.…”

Section: Discussionmentioning

confidence: 99%

An integrative analysis of reprogramming in human isogenic system identified a clone selection criterion

et al. 2016

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Kiselev (2016) An integrative analysis of reprogramming in human isogenic system identified a clone selection criterion, Cell Cycle, 15:7, 986-997, DOI: 10.1080/15384101.2016 ABSTRACTThe pluripotency of newly developed human induced pluripotent stem cells (iPSCs) is usually characterized by physiological parameters; i.e., by their ability to maintain the undifferentiated state and to differentiate into derivatives of the 3 germ layers. Nevertheless, a molecular comparison of physiologically normal iPSCs to the "gold standard" of pluripotency, embryonic stem cells (ESCs), often reveals a set of genes with different expression and/or methylation patterns in iPSCs and ESCs. To evaluate the contribution of the reprogramming process, parental cell type, and fortuity in the signature of human iPSCs, we developed a complete isogenic reprogramming system. We performed a genome-wide comparison of the transcriptome and the methylome of human isogenic ESCs, 3 types of ESC-derived somatic cells (fibroblasts, retinal pigment epithelium and neural cells), and 3 pairs of iPSC lines derived from these somatic cells. Our analysis revealed a high input of stochasticity in the iPSC signature that does not retain specific traces of the parental cell type and reprogramming process. We showed that 5 iPSC clones are sufficient to find with 95% confidence at least one iPSC clone indistinguishable from their hypothetical isogenic ESC line. Additionally, on the basis of a small set of genes that are characteristic of all iPSC lines and isogenic ESCs, we formulated an approach of "the best iPSC line" selection and confirmed it on an independent dataset.

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Transplantation of Embryonic and Induced Pluripotent Stem Cell-Derived 3D Retinal Sheets into Retinal Degenerative Mice

Cited by 318 publications

References 34 publications

Characterization of Three-Dimensional Retinal Tissue Derived from Human Embryonic Stem Cells in Adherent Monolayer Cultures

Characterization of Three-Dimensional Retinal Tissue Derived from Human Embryonic Stem Cells in Adherent Monolayer Cultures

Differentiation of human embryonic stem cells into cone photoreceptors through simultaneous inhibition of BMP, TGFβ and Wnt signaling

An integrative analysis of reprogramming in human isogenic system identified a clone selection criterion

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