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Nicotinamide promotes formation of retinal organoids from human pluripotent stem cells via enhanced neural cell fate commitment

ABSTRACT: Nicotinamide promotes formation of retinal organoids from human pluripotent stem cells via enhanced neural cell fate commitment

PROVIDER: PRJNA692366 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13442846_1.fastq.gz	Fastqsanger.gz
	SRR13442846_2.fastq.gz	Fastqsanger.gz
	SRR13442847_1.fastq.gz	Fastqsanger.gz
	SRR13442847_2.fastq.gz	Fastqsanger.gz
	SRR13442848_1.fastq.gz	Fastqsanger.gz

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Nicotinamide promotes formation of retinal organoids from human pluripotent stem cells via enhanced neural cell fate commitment

Project description:Retinal organoids (ROs) derived from human pluripotent stem cells (hPSCs) recapitulate key features of human retinogenesis and thus provide a promising platform to study the mechanisms of retinal development and disease in a human context and to evaluate therapies. Although multiple differentiation protocols are currently in use, hPSCs exhibit tremendous variability in differentiation efficiency, with some cell lines consistently yielding few or even no ROs thus limiting their utility in research. To improve the efficiency and robustness of RO generation, we set out to identify factors that promote neural retina differentiation from hPSCs. We report here that nicotinamide (NAM) treatment at the early stage of differentiation significantly improved RO yield across 8 hPSC lines from different donors. Importantly, NAM treatment enabled efficient production of ROs from cell lines that would otherwise fail to generate meaningful number of ROs. Further analyses revealed that NAM treatment promotes neural commitment of hPSCs at the expense of non-neural ectodermal cell fate, which in turn increases eye field commitment and RO generation. This effect is mediated, at least in part, through inhibition of BMP signaling. Thus, our modified protocol with a simple NAM treatment improves the yield of ROs in all lines tested, and importantly greatly benefits to cell lines that previously proved to be intractable in retinal differentiation. Our data should facilitate the broader use of human ROs for disease modeling applications requiring the use of multiple cell lines or a larger scale of cell source such as therapy screening.

2022-06-14 | GSE164884 | GEO

Nicotinamide Promotes Formation of Retinal Organoids From Human Pluripotent Stem Cells <i>via</i> Enhanced Neural Cell Fate Commitment.

Project description:Retinal organoids (ROs) derived from human pluripotent stem cells (hPSCs) recapitulate key features of retinogenesis and provide a promising platform to study retinal development and disease in a human context. Although multiple protocols are currently in use, hPSCs exhibit tremendous variability in differentiation efficiency, with some cell lines consistently yielding few or even no ROs, limiting their utility in research. We report here that early nicotinamide (NAM) treatment significantly improves RO yield across 8 hPSC lines from different donors, including some that would otherwise fail to generate a meaningful number of ROs. NAM treatment promotes neural commitment of hPSCs at the expense of non-neural ectodermal cell fate, which in turn increases eye field progenitor generation. Further analysis suggests that this effect is partially mediated through inhibition of BMP signaling. Our data encourage a broader use of human ROs for disease modeling applications that require the use of multiple patient-specific cell lines.

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ETV2 primes hematoendothelial gene enhancers prior to hematoendothelial fate commitment

Project description:The lineage-determining transcription factor ETV2 is necessary and sufficient for hematoendothelial fate commitment. We investigated how ETV2-driven gene regulatory networks promote hematoendothelial fate commitment. We resolved the sequential determination steps of hematoendothelial versus cardiac differentiation from mouse embryonic stem cells. Etv2 was strongly induced and bound to the enhancers of hematoendothelial genes in a common cardiomyocyte-hematoendothelial mesoderm progenitor. However, only Etv2 itself and Tal1, not other ETV2-bound genes, were induced. Despite ETV2 genomic binding and Etv2 and Tal1 expression, cardiomyogenic fate potential was maintained. A second wave of ETV2-bound target genes was up-regulated during the transition from the common cardiomyocyte-hematoendothelial progenitor to the committed hematoendothelial population. A third wave of ETV-bound genes were subsequently expressed in the committed hematoendothelial population for sub-lineage differentiation. The shift from ETV2 binding to productive transcription, not ETV2 binding to target gene enhancers, drove hematoendothelial fate commitment. This work identifies mechanistic phases of ETV2-dependent gene expression that distinguish hematoendothelial specification, commitment, and differentiation.

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PHLDA1-PRDM1 mediates the effect of lentiviral vectors on fate-determination of human retinal progenitor cells

Project description:Lentiviral vectors have markedly enhanced gene therapy efficiency in treating congenital diseases, but its long-term safety remains controversial. Most gene therapies for congenital eye diseases need to be carried out at early ages, yet the assessment of related risks to ocular development posed by lentiviral vectors is challenging. Utilizing single-cell transcriptomic profiling on human retinal organoids, this study explored the impact of lentiviral vectors on the retinal development and found that lentiviral vectors can cause retinal precursor cells to shift toward photoreceptor fate through the up-regulation of key fate-determining genes such as PRDM1. Further investigation demonstrated that the intron and intergenic region of PRDM1 was bound by PHLDA1, which was also upregulated by lentiviral vector exposure. Importantly, knockdown of PHLDA1 successfully suppressed the lentivirus-induced differentiation bias of photoreceptor cells. The findings also suggest that while lentiviral vectors may disrupt the fate determination of retinal precursor cells, posing risks in early-stage retinal gene therapy, these risks could potentially be reduced by inhibiting the PHLDA1-PRDM1 signaling axis.

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Genome-wide ChIP-seq analysis of Pou3f1 during mouse pluripotent stem cell neural fate commitment

Project description:Appropriate neural initiation of the pluripotent stem cells in the early embryos is critical for the development of the central nervous system. This process is regulated by the coordination of extrinsic signals and intrinsic programs. However, how the coordination is achieved to ensure proper neural fate commitment is largely unknown. Here, taking advantage of genome-wide ChIP-sequencing (ChIP-seq) and RNA-sequencing (RNA-seq) analyses, we demonstrate that the transcriptional factor Pou3f1 is an upstream activator of neural-promoting genes, and it is able to repress neural-inhibitory signals as well. Further studies revealed that Pou3f1 could directly bind neural lineage genes like Sox2 and downstream targets of neural inhibition signaling such as BMP and Wnt. Our results thus identify Pou3f1 as a critical dual-regulator of the intrinsic transcription factors and the extrinsic cellular signals during neural fate commitment. ChIP-seq assay was ultilized to characterize the targets of Pou3f1 on ESC differentiation day 2.

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thrombopoietin-induced megakaryocyte differentiation with and without nicotinamide

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Zeb2 regulates commitment to plasmacytoid dendritic cell and monocyte fate

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ETV2 primes hematoendothelial gene enhancers prior to hematoendothelial fate commitment

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