Podocalyxin-Like Protein 1 Regulates Extended and Primed Pluripotency through the Cholesterol Biosynthesis Pathway
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA781192 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16964669_1.fastq.gz | Fastqsanger.gz | |||
| SRR16964669_2.fastq.gz | Fastqsanger.gz | |||
| SRR16964670_1.fastq.gz | Fastqsanger.gz | |||
| SRR16964670_2.fastq.gz | Fastqsanger.gz |
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Project description:Deciphering signaling mechanisms critical for the extended pluripotent stem cell (EPSC) state and primed pluripotency is necessary for understanding embryonic development. Here, we identify a membrane protein, Podocalyxin-like protein 1 (PODXL) as being essential for extended and primed pluripotency. Alteration of PODXL expression levels affects self-renewal, protein expression of c-MYC and telomerase, and induced pluripotent stems cell (iPSC) and EPSC colony formation. PODXL is the first membrane protein reported to regulate de novo cholesterol biosynthesis, and human pluripotent stem cells (hPSCs) are more sensitive to cholesterol depletion than fibroblasts. The addition of exogenous cholesterol fully restores PODXL knockdown-mediated loss of pluripotency. PODXL affects lipid raft dynamics via the regulation of cholesterol. PODXL recruits the RAC1/CDC42/actin network to regulate SREBP1 and SREBP2 maturation and lipid raft dynamics. Single-cell RNA sequencing reveals PODXL overexpression enhanced chimerism between human cells in mouse host embryos (hEPSCs 57%). Interestingly, in the human-mouse chimeras, laminin and collagen signaling-related pathways are dominant in PODXL overexpressing cells. We conclude that cholesterol regulation via PODXL signaling is critical for ESC/EPSC.
2022-09-22 | GSE213618 | GEO
Project description:Podocalyxin-Like Protein 1 Regulates Pluripotency through the Cholesterol Biosynthesis Pathway
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Project description:We utilized scRNA-seq to study the human-mouse chimera transcriptomic regulation at peri-implantation embryo stage. Single-cell RNA sequencing revealed PODXL overexpression boosted chimerism between human cells in mouse host embryos and the potential cell-cell communication interactions in human-mouse chimeras. Potential cell-cell communications were identified to optimize cell-cell contact interaction for reducing the xenogeneic barrier in the interspecies chimeras in future studies.
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Project description:Deciphering signaling mechanisms critical for the extended pluripotent stem cell (EPSC) state and primed pluripotency is necessary for understanding embryonic development. Here, a membrane protein, podocalyxin-like protein 1 (PODXL) as being essential for extended and primed pluripotency, is identified. Alteration of PODXL expression levels affects self-renewal, protein expression of c-MYC and telomerase, and induced pluripotent stem cell (iPSC) and EPSC colony formation. PODXL is the first membrane protein reported to regulate de novo cholesterol biosynthesis, and human pluripotent stem cells (hPSCs) are more sensitive to cholesterol depletion than fibroblasts. The addition of exogenous cholesterol fully restores PODXL knockdown-mediated loss of pluripotency. PODXL affects lipid raft dynamics via the regulation of cholesterol. PODXL recruits the RAC1/CDC42/actin network to regulate SREBP1 and SREBP2 maturation and lipid raft dynamics. Single-cell RNA sequencing reveals PODXL overexpression enhanced chimerism between human cells in mouse host embryos (hEPSCs 57%). Interestingly, in the human-mouse chimeras, laminin and collagen signaling-related pathways are dominant in PODXL overexpressing cells. It is concluded that cholesterol regulation via PODXL signaling is critical for ESC/EPSC.
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Project description:Embryo implantation is a key step in establishing pregnancy and a major limiting factor in IVF. Implantation requires the endometrium, the inner lining of the uterus, to transform from a non-receptive to a receptive state, to allow embryos to attach to the surface and enter into the tissue. However, the fundamental mechanisms governing receptivity are not well understood. Here we show that transmembrane protein podocalyxin is a major and clinically significant factor regulating human endometrial receptivity. Podocalyxin is expressed in all endometrial epithelial cells in the non-receptive state but is selectively down-regulated in the luminal epithelium at receptivity. We present evidence that podocalyxin critically governs the barrier function of the endometrial epithelium, likely as an intrinsic protective mechanism, rendering it non-receptive to an embryo. In addition, podocalyxin suppresses genes promoting receptivity (eg LIF, CSF1) but stimulates those inhibiting implantation (eg WNT7A, LEFTY2). Down-regulation of podocalyxin in the luminal epithelium, likely mediated by progesterone, selectively converts the endometrial surface to a more adhesive state that facilitates embryo attachment and penetration. Furthermore, inadequate down-regulation of podocalyxin in the endometrial luminal epithelium is associated with poorer implantation rates in IVF. We thus propose that podocalyxin promotes the barrier function of human endometrial epithelial cells and critically regulates receptivity for embryo implantation.
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Project description:The transmembrane signals maintain the pluripotency of human pluripotent stem cells (hPSCs) are rarely investigated. A transmembrane glycoprotein, podocalyxin-like protein 1 (PODXL, also called podocalyxin like protein-1, PCLP1, Gp200/GCTM-2, MEP21, and Thrombomucin), aside from its well-known role in tumor malignancy, very little is known about its functions in hPSCs. In order to map the early signals triggered by PODXL, after 3 days of PODXL overexpression, a comprehensive gene expression profile changes were analyzed by cDNA microarray.
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