Identification of ALPPL2 as a novel specific and functional surface marker for naïve pluripotency
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA656543 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12430700_1.fastq.gz | Fastqsanger.gz | |||
| SRR12430700_2.fastq.gz | Fastqsanger.gz | |||
| SRR12430701_1.fastq.gz | Fastqsanger.gz | |||
| SRR12430701_2.fastq.gz | Fastqsanger.gz | |||
| SRR12430703_1.fastq.gz | Fastqsanger.gz |
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Project description:We report ALPPL2 as a prominently specific and functional surface marker for naïve pluripotency. By performing RNA-seq analysis of TJ-1# and iCRISPR nESCs and pESCs, APG+ cells at different time points during naïve reprogramming, we validate ALPPL2’s specificity for naïve pluripotent state at transcriptional level. Deep analysis of the transcriptome differences between Wild Type (WT), ALPPL2 knockdown (AKD) cells via RNA-seq, Wild Type (WT), ALPPL2 knockout (AKO) and IGFBP1 knockout (IKO) individual colonies in detail via Smart-seq, and performing RNA immunoprecipitation (RIP) using IGF2BP1 antibody in nESCs followed by RNA-seq or qPCR analysis, we identify that ALPPL2 is essential for both establishment and maintenance of naïve pluripotency via interacting with IGF2BP1 to stabilize TFCP2L1 and STAT3 mRNA level.
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Project description:Derivation of human naïve cells in the ground state of pluripotency provides promising avenues for developmental studies and therapeutic manipulations. However, the molecular mechanisms involved in establishment and maintenance of human naïve pluripotency remain poorly understood. Using the human inducible reprogramming system together with 5iLAF naïve induction strategy, we performed integrative analysis across the timeline from human fibroblasts to naïve iPSCs, which reveals ordered expression waves of gene networks sharing signatures with embryonic development process from post-implantation to pre-implantation stages. We also observed a significant transient re-activation of transcripts with 8-cell-stage-like characteristics in late naïve reprogramming stages. Moreover, combined quantitative proteomics analysis with transcriptional dynamics during naïve pluripotency induction, we identified ALPPL2 as the specific surface marker for human naïve pluripotency. Altogether, our study deepens the understanding of molecular mechanisms of human naïve pluripotency.
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Project description:Derivation of human naïve cells in the ground state of pluripotency provides promising avenues for developmental studies and therapeutic manipulations. However, the molecular mechanisms involved in establishment and maintenance of human naïve pluripotency remain poorly understood. Using the human inducible reprogramming system together with 5iLAF naïve induction strategy, we performed integrative analysis across the timeline from human fibroblasts to naïve iPSCs, which reveals ordered expression waves of gene networks sharing signatures with embryonic development process from post-implantation to pre-implantation stages. We also observed a significant transient re-activation of transcripts with 8-cell-stage-like characteristics in late naïve reprogramming stages. Moreover, combined quantitative proteomics analysis with transcriptional dynamics during naïve pluripotency induction, we identified ALPPL2 as the specific surface marker for human naïve pluripotency. Altogether, our study deepens the understanding of molecular mechanisms of human naïve pluripotency.
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Project description:Derivation of human naïve cells in the ground state of pluripotency provides promising avenues for developmental studies and therapeutic manipulations. However, the molecular mechanisms involved in establishment and maintenance of human naïve pluripotency remain poorly understood. Using the human inducible reprogramming system together with 5iLAF naïve induction strategy, we performed integrative analysis across the timeline from human fibroblasts to naïve iPSCs, which reveals ordered expression waves of gene networks sharing signatures with embryonic development process from post-implantation to pre-implantation stages. We also observed a significant transient re-activation of transcripts with 8-cell-stage-like characteristics in late naïve reprogramming stages. Moreover, combined quantitative proteomics analysis with transcriptional dynamics during naïve pluripotency induction, we identified ALPPL2 as the specific surface marker for human naïve pluripotency. Altogether, our study deepens the understanding of molecular mechanisms of human naïve pluripotency.
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Project description:In contrast to conventional human pluripotent stem cells (hPSC) that are related to post-implantation embryo stages, naïve hPSC exhibit features of pre-implantation epiblast. Naïve hPSC are established by resetting conventional hPSC, or are derived from dissociated embryo inner cell masses. Here we investigate conditions for transgene-free reprogramming of human somatic cells to naïve pluripotency. We find that RNA-mediated induction of naïve pluripotency is enhanced by Wnt inhibition. We demonstrate application to independent human fibroblast cultures and endothelial progenitor cells and show that induced naïve hPSC can be clonally expanded with a diploid karyotype. They exhibit distinctive surface marker, transcriptome, and methylome properties of naïve epiblast identity. Induced naïve hPSC lines undergo somatic lineage differentiation following formative transition. Efficient, facile, and reliable induction of transgene free naïve hPSC offers a robust platform for delineation of human reprogramming trajectories and for evaluating the attributes of isogenic naïve versus conventional hPSC.
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Project description:Although cell therapies require large numbers of quality-controlled hPSCs, existing technologies are limited in their ability to efficiently grow and scale stem cells. We report here that cell-state conversion from primed-to-naïve pluripotency enhances the biomanufacturing of hPSCs. Naïve hPSCs exhibit superior growth kinetics and aggregate formation characteristics in stirred suspension bioreactors compared to their primed counterparts. Moreover, we demonstrate the role of the bioreactor mechanical environment in the maintenance of naïve pluripotency, through transcriptomic enrichment of mechano-sensing signaling for cells in the bioreactor along with a decrease in expression of lineage-specific and primed pluripotency hallmarks. Bioreactor-cultured, naïve hPSCs maintain epigenetic hallmarks of naïve pluripotency, exhibit robust production of naïve pluripotency metabolites, and display reduced expression of primed pluripotency cell surface markers. We also show that these cells retain the ability to undergo targeted differentiation into beating cardiomyocytes, hepatocytes and neural rosettes. They additionally display faster kinetics of teratoma formation compared to their primed counterparts. Naïve bioreactor hPSCs also retain structurally stable chromosomes. Our research corroborates that converting hPSCs to the naïve state enhances hPSC manufacturing and indicates a potentially important role for the bioreactor’s mechanical environment in maintaining naïve pluripotency.
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Project description:Epigenetic reprogramming is a cancer hallmark but how it unfolds during early neoplastic events and its role in carcinogenesis and cancer progression is not fully understood. Here we show that resetting from primed to naïve human pluripotency results in acquisition of a DNA methylation landscape mirroring the cancer DNA methylome, with gradual hypermethylation of bivalent developmental genes. We hypothesised that unknown proteins and transcription factors play a role in the DNA hypermethylation process and analysed therefore the proteomics of the very early stages of the resetting process which involves overexpression of Nanog and Klf2. The samples analysed were Primed hESCs (Conventional stem cells), 72hours after induction and 1 week after induction, in triplicate. For our purposes we identified candidate transcription factors and subsequently knocked them down to test their involvement in the DNA hypermethylation (as described in the manuscript related to this data, Patani et al. Nature Communications). More broadly, we believe, this dataset is a useful resource for the wider community interested in pluripotency, resetting, reprogramming, cell identity transitions etc. Our results indicate that transition to naïve pluripotency and oncogenic transformation share common epigenetic trajectories, which implicates reprogramming and the pluripotency network as a central hub in cancer formation.
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