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PAX6D instructs neural retinal specification from human embryonic stem cell-derived neuroectoderm.

ABSTRACT: PAX6 is essential for neural retina (NR) and forebrain development but how PAX6 instructs NR versus forebrain specification remains unknown. We found that the paired-less PAX6, PAX6D, is expressed in NR cells during human eye development and along human embryonic stem cell (hESC) specification to retinal cells. hESCs deficient for PAX6D failed to enter NR specification. Induced expression of PAX6D but not PAX6A in a PAX6-null background restored the NR specification capacity. ChIP-Seq, confirmed by functional assays, revealed a set of retinal genes and non-retinal neural genes that are potential targets of PAX6D, including WNT8B. Inhibition of WNTs or knocking down of WNT8B restored the NR specification capacity of neuroepithelia with PAX6D knockout, whereas activation of WNTs blocked NR specification even when PAX6D was induced. Thus, PAX6D specifies neuroepithelia to NR cells via the regulation of WNT8B.

SUBMITTER: Tao Y

PROVIDER: S-EPMC7507545 | biostudies-literature |

REPOSITORIES: biostudies-literature

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PAX6D Instructs Neural Retinal Specification from Human Embryonic Stem Cell-Derived Neuroectoderm

Project description:PAX6 is essential for neural retina (NR) and forebrain development but how PAX6 instructs NR versus forebrain specification remains unknown. We found that the paired-less PAX6, PAX6D, is expressed in NR cells during human eye development and along human embryonic stem cell (hESC) specification to retinal cells. hESCs deficient for PAX6D failed to enter NR specification. Induced expression of PAX6D but not PAX6A in a PAX6-null background restored the NR specification capacity. ChIP-Seq, confirmed by functional assays, revealed a set of retinal genes and non-retinal neural genes that are potential targets of PAX6D, including WNT8B. Inhibition of WNTs or knocking down of WNT8B restored the NR specification capacity of neuroepithelia with PAX6D knockout whereas activation of WNTs blocked NR specification even when PAX6D was induced. Thus, PAX6D specifies neuroepithelia to NR cells via regulation of WNT8B.

| S-SCDT-EMBOR-2020-50000V1 | biostudies-other

PAX6D instructs neural retinal specification from human embryonic stem cell-derived neuroectoderm

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-07-11 | GSE128141 | GEO

PAX6D instructs neural retinal specification from human embryonic stem cell-derived neuroectoderm

Project description:PAX6D instructs neural retinal specification from human embryonic stem cell-derived neuroectoderm

| PRJNA526532 | ENA

Nicotinamide rescues human embryonic stem cell-derived neuroectoderm from parthanatic cell death.

Project description:Abundant cell death is observed when human embryonic stem cells (hESCs) undergo neuralization, a critical first step for future cell-based therapies addressing neurodegeneration. Using hESC neuralization as an in vitro model of human development, we demonstrated that the developing neuroepithelium acquires increased susceptibility to spontaneous cell death. We found that poly(ADP-ribose) polymerase-1 (PARP1)/apoptosis-inducing factor (AIF)-mediated cell death (parthanatos) is a dominant mechanism responsible for cell loss during hESC neuralization. The demise of neural progenitor cells, at least in part, is due to decreased endogenous antioxidant defenses and enhanced reactive oxygen species leakage from mitochondria fuelled by nonphysiological culture conditions. Under such conditions, PARP1 overactivation triggered cell death through the mitochondrial-nuclear translocation of AIF. Blocking PARP1 activity with small hairpin RNA interference or nicotinamide dramatically enhanced hESC neuralization, providing optimal survival of the developing neuroepithelium. Because nicotinamide is a physiological metabolite, our results raise the possibility that neural stem/progenitor cell survival in vivo requires a metabolic niche. We argue that small natural metabolites provide a powerful physiological tool to optimize hESC differentiation compatible with the requirements of regenerative medicine.

| S-EPMC4151857 | biostudies-literature

Microarray characterization of human embryonic stem cell--derived retinal cultures.

Project description:PurposeA number of protocols have been published to induce retinal determination from human embryonic stem cells (hESC) and induced pluripotent stem cells (iPSC). Although all these studies have shown some degree of expression of markers of retinal cells, fewer than 30 markers are typically used to characterize the ESC-derived retinal cells. Hence, it is not known whether they express all the genes present in normal developing retinal cells. To assess the efficiency of their retinal determination protocol at the transcriptome level and to understand the changes in human retinal gene expression patterns during development, the authors conducted a microarray-based analysis comparing human retina to hESC-derived retinal cells.MethodsThe authors extracted total RNA from 60-day, 80-day, and 96-day human fetal retina and hESC-derived retinal cells at 3 weeks and 9 weeks after induction. RNA was subjected to analysis using a commercial microarray. Data were normalized using Affymetrix Power Tools and analyzed using commercial microarray software.ResultsOn K-median clustering analysis, the authors found that overall there was a very high correlation between genes expressed in human fetal retina and those in ESC-derived retinal cultures. The cultures were at similar developmental ages to the corresponding fetal retinal ages. They found only 1% of the genes on the array to be expressed at a higher level in ESC-derived retinal cells than in fetal retina, and most of these were expressed in the retinal pigment epithelium and ciliary epithelium.ConclusionsIn sum, gene array profiling provides an effective method for characterization of the efficiency of directed differentiation of hESCs to retinal cells.

| S-EPMC3175935 | biostudies-literature

Modeling human retinoblastoma using embryonic stem cell-derived retinal organoids.

Project description:Retinoblastoma (Rb) is the most prevalent intraocular malignancy in early childhood. Traditional models are unable to accurately recapitulate the origin and development of human Rb. Here, we present a protocol to establish a novel human Rb organoid (hRBO) model derived from genetically engineered human embryonic stem cells (hESCs). This hRBO model exhibits properties highly consistent with human primary Rb and can be used effectively for dissecting the origination and pathogenesis of Rb as well as for screening of potential therapies. For complete details on the use and execution of this protocol, please refer to Liu et al. (2020).

| S-EPMC8058612 | biostudies-literature

Role of RB1 in human embryonic stem cell-derived retinal organoids.

Project description:Three-dimensional (3D) organoid models derived from human pluripotent stem cells provide a platform for studying human development and understanding disease mechanisms. Most studies that examine biallelic inactivation of the cell cycle regulator Retinoblastoma 1 (RB1) and the link to retinoblastoma is in mice, however, less is known regarding the pathophysiological role of RB1 during human retinal development. To study the role of RB1 in early human retinal development and tumor formation, we generated retinal organoids from CRISPR/Cas9-derived RB1-null human embryonic stem cells (hESCs). We showed that RB is abundantly expressed in retinal progenitor cells in retinal organoids and loss of RB1 promotes S-phase entry. Furthermore, loss of RB1 resulted in widespread apoptosis and reduced the number of photoreceptor, ganglion, and bipolar cells. Interestingly, RB1 mutation in retinal organoids did not result in retinoblastoma formation in vitro or in the vitreous body of NOD/SCID immunodeficient mice. Together, our work identifies a crucial function for RB1 in human retinal development and suggests that RB1 deletion alone is not sufficient for tumor development, at least in human retinal organoids.

| S-EPMC7314500 | biostudies-literature

Deterministic HOX patterning in human pluripotent stem cell-derived neuroectoderm.

Project description:Colinear HOX expression during hindbrain and spinal cord development diversifies and assigns regional neural phenotypes to discrete rhombomeric and vertebral domains. Despite the precision of HOX patterning in vivo, in vitro approaches for differentiating human pluripotent stem cells (hPSCs) to posterior neural fates coarsely pattern HOX expression thereby generating cultures broadly specified to hindbrain or spinal cord regions. Here, we demonstrate that successive activation of fibroblast growth factor, Wnt/?-catenin, and growth differentiation factor signaling during hPSC differentiation generates stable, homogenous SOX2(+)/Brachyury(+) neuromesoderm that exhibits progressive, full colinear HOX activation over 7 days. Switching to retinoic acid treatment at any point during this process halts colinear HOX activation and transitions the neuromesoderm into SOX2(+)/PAX6(+) neuroectoderm with predictable, discrete HOX gene/protein profiles that can be further differentiated into region-specific cells, e.g., motor neurons. This fully defined approach significantly expands capabilities to derive regional neural phenotypes from diverse hindbrain and spinal cord domains.

| S-EPMC4400649 | biostudies-literature

E2A regulates neural ectoderm fate specification in human embryonic stem cells.

Project description:E protein transcription factors are crucial for many cell fate decisions. However, the roles of E proteins in the germ-layer specification of human embryonic stem cells (hESCs) are poorly understood. We disrupted the TCF3 gene locus to delete the E protein E2A in hESCs. E2A knockout (KO) hESCs retained key features of pluripotency, but displayed decreased neural ectoderm coupled with enhanced mesoendoderm outcomes. Genome-wide analyses showed that E2A directly regulates neural ectoderm and Nodal pathway genes. Accordingly, inhibition of Nodal or E2A overexpression partially rescued the neural ectoderm defect in E2A KO hESCs. Loss of E2A had little impact on the epigenetic landscape of hESCs, whereas E2A KO neural precursors displayed increased accessibility of the gene locus encoding the Nodal agonist CRIPTO. Double-deletion of both E2A and HEB (TCF12) resulted in a more severe neural ectoderm defect. Therefore, this study reveals critical context-dependent functions for E2A in human neural ectoderm fate specification.

| S-EPMC7758636 | biostudies-literature

Immunological Properties of Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells.

Project description:Age-related macular degeneration is caused by dysfunction and loss of retinal pigment epithelium (RPE) cells, and their transplantation may rescue visual functions and delay disease progression. Human embryonic stem cells (hESCs) may be an unlimited source of RPE cells for allotransplantation. We analyzed the immunomodulatory properties of hESC-derived RPE (hESC-RPE) cells, and showed that they inhibited T cell responses. Co-culture experiments showed that RPE cells inhibited interfon-? secretion and proliferation of activated T cells. Furthermore, hESC-RPE cells enhanced T cell apoptosis and secretion of the anti-inflammatory cytokine interleukin-10 (IL-10). In addition, RPE cells altered the expression of T cell activation markers, CD69 and CD25. RPE cells transplanted into RCS rats without immunosuppression survived, provided retinal rescue, and enhanced IL-10 blood levels. Our data suggest that hESC-RPE cells have immunosuppressive properties. Further studies will determine if these properties are sufficient to alleviate the need for immunosuppression therapy after their clinical allotransplantation.

| S-EPMC6135721 | biostudies-literature

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