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Wnt Activation and Dual SMAD Inhibition For Induction and Maintenance of Hindbrain-like Neural Stem Cell from hiPSCs [scRNA-seq]

ABSTRACT: Neurons exhibit region-specific identities corresponding to functional distinctions across different brain areas. Region-restricted neural stem cells (NSCs) have previously been generated from pluripotent stem cells; however, maintaining their regional identity over extended passages remains challenging. Here, we report the generation of hindbrain-like induced NSCs (Hb-LiNSCs) with upregulated hindbrain-specific markers and downregulated forebrain, midbrain, and spinal cord markers under xeno- and basic fibroblast growth factor-free conditions using three chemicals—CHIR99021 (at a high concentration), a potent activator of the Wnt pathway, A-83-01, a potent inhibitor of the TGF-β/Activin/Nodal pathway, and LDN193189, a potent inhibitor of the bone morphogenetic protein pathway. Hb-LiNSCs maintained their chromosomal integrity, multipotency, and differentiation capacity even after long-term culture for more than 60 weeks. This innovative approach enhances our understanding of neurodevelopmental and neurodegenerative processes in the hindbrain region and paves the way for developing targeted cell-based therapy as well as disease modeling for drug discovery.

ORGANISM(S): Homo sapiens

PROVIDER: GSE317025 | GEO | 2026/01/27

REPOSITORIES: GEO

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Wnt Activation and Dual SMAD Inhibition For Induction and Maintenance of Hindbrain-like Neural Stem Cell from hiPSCs [RNA-Seq]

Project description:Neurons exhibit region-specific identities corresponding to functional distinctions across different brain areas. Region-restricted neural stem cells (NSCs) have previously been generated from pluripotent stem cells; however, maintaining their regional identity over extended passages remains challenging. Here, we report the generation of hindbrain-like induced NSCs (Hb-LiNSCs) with upregulated hindbrain-specific markers and downregulated forebrain, midbrain, and spinal cord markers under xeno- and basic fibroblast growth factor-free conditions using three chemicals—CHIR99021 (at a high concentration), a potent activator of the Wnt pathway, A-83-01, a potent inhibitor of the TGF-β/Activin/Nodal pathway, and LDN193189, a potent inhibitor of the bone morphogenetic protein pathway. Hb-LiNSCs maintained their chromosomal integrity, multipotency, and differentiation capacity even after long-term culture for more than 60 weeks. This innovative approach enhances our understanding of neurodevelopmental and neurodegenerative processes in the hindbrain region and paves the way for developing targeted cell-based therapy as well as disease modeling for drug discovery.

2026-01-29 | GSE317319 | GEO

Secreted STIP1 stimulates cell proliferation of ovarian cancer through SMAD signaling pathways

Project description:Stress-induced phosphoprotein 1 (STIP1) is a co-chaperone that regulates other chaperone proteins that was recently shown to be secreted by ovarian cancer cells to induce cell proliferation. In this study, we found that STIP1 induced the phosphorylation of endogenous SMAD1/5, and knockdown of SMAD1/4/5 blocked STIP1-activated ID3 expression. Inhibition of ALK2, a serine/threonine kinase receptor, with siRNA or the specific inhibitor LDN193189, blocked STIP1-induced phosphorylation of SMAD1/5 and inhibited STIP1-related cell proliferation. The signaling pathway was found to involve binding of secreted STIP1 to ALK2, phosphorylation of SMAD, and activation of ID3 to induce cell proliferation was identified not only by in vitro immunofluorescent microscopy and biochemical identification of complex formation, but also by in vivo immunohistochemical analyses of ovarian cancer tissues. MDAH2774 cell treated with rhSTIP1 MDAH2774 cell treated without rhSTIP1 MDAH2774 cell treated with rhSTIP1-2 MDAH2774 cell treated without rhSTIP1-2

2012-03-03 | E-GEOD-27654 | biostudies-arrayexpress

Secreted STIP1 stimulates cell proliferation of ovarian cancer through SMAD signaling pathways

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System-wide biochemical analysis reveals ozonide and artemisinin antimalarials initially act by disrupting malaria parasite haemoglobin digestion

Project description:Artemisinins are currently the first-line antimalarials, and rely on a peroxide pharmacophore for their potent activity. OZ277 (arterolane) and OZ439 (artefenomel) are newer synthetic peroxide-based antimalarials with potent activity against the deadliest malaria parasite, Plasmodium falciparum. Here we used a “multi-omics” workflow, in combination with activity-based protein profiling (ABPP), to demonstrate that peroxide antimalarials initially target the haemoglobin (Hb) digestion pathway to kill malaria parasites. Time-dependent metabolomic profiling of peroxide-treated P. falciparum infected red blood cells (iRBCs) revealed a rapid depletion of short Hb-derived peptides, while untargeted peptidomics showed accumulation of longer Hb peptides. Quantitative proteomics and ABPP assays demonstrated that Hb digesting proteases were significantly increased in abundance and activity following treatment, respectively. The association between peroxide activity and Hb catabolism was also confirmed in a K13-mutant artemisinin resistant parasite line. To demonstrate that compromised Hb catabolism may be a primary mechanism involved in peroxide antimalarial activity, we showed that parasites forced to rely solely on Hb digestion for amino acids became hypersensitive to short peroxide exposures. Quantitative proteomics analysis also revealed parasite proteins involved in translation and the ubiquitin-proteasome system were enriched following drug treatment, suggestive of the parasite engaging a stress response to mitigate peroxide-induced damage. Taken together, these data point to a mechanism of action involving initial impairment of Hb catabolism, and indicate that the parasite regulates protein turnover to manage peroxide-induced damage.

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Transcriptomic heterogeneity of quiescent neural stem cells underlies distinct reactivation routes and potential upon Notch signaling blockade

Project description:Adult Neural Stem Cells (NSCs) are glial cells that remain mostly quiescent but periodically activate to support neurogenesis throughout life in many species. It has progressively become clear that NSCs are heterogeneous and that the stem cell pool is in fact made up of distinct subpopulations. In zebrafish these subpopulations were recently characterized, identifying sets of molecular markers that can reliably identify subpopulations. Based on in sillico analysis and in particular the relative expression of gene sets associated either with deep quiescence or activation these subpopulations were predicted to possess distinct quiescence depths, however this prediction has not been challenged experimentally. The Notch pathway is known as a major regulator opromoting NSC quiescence in several species. Here, we used LY-411575, a potent Notch Pathway inhibitor, and treated zebrafish for 24h to push NSCs towards activation before sacrifing the fish and collecting the telencephalon, with the goal of comparing the transcriptomes of NSCs and their immediate progeny with or without LY treatment and determine whether predicted quiescence depth of NSC subpopulations does correlate with distinct responses to a pro-activation stimulus.

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Postmortem gene expression profiles in the habenulae of suicides: Implication of endothelial dysfunction in the neurovascular system

Project description:The habenula (Hb) is an epithalamic structure that links multiple forebrain areas with the mid/hindbrain monoaminergic systems. As an anti-reward center, it has been implicated in the etiology of various neuropsychiatric disorders, particularly those associated with dysregulated reward circuitry. In this regard, Hb has been proposed as a therapeutic target for treatment-resistant depression associated with a higher risk of suicide. Therefore, we aimed to gain insight into the molecular signatures of the Hb in association with suicide in individuals with major depression. Postmortem gene expression analysis identified 251 differentially expressed genes (DEGs) in the Hb tissue of suicides in comparison with Hb tissues from neurotypical individuals. Subsequent bioinformatic analyses using single-cell data from the mouse Hb showed that the levels of a subset of endothelial cell-enriched genes encoding cell-cell junctional complex and plasma membrane-associated proteins, as well as the levels of their putative upstream transcriptional regulators, were significantly affected in suicides. Taken together, the present study suggests a potential association of endothelial dysfunction in the Hb with depression and suicidal behavior. although our findings are based on a limited sample of individuals.

2022-06-01 | GSE199536 | GEO

TTNPB Promotes Pluripotent-to-Neural Stem Cell Transition through Modulating Chromatin Accessibility and Choline Metabolism [ATAC-seq]

Project description:Efficient derivation of neural stem cells (NSCs) from human pluripotent stem cells (PSCs) is crucial for developmental biology and regenerative medicine. Here, we established a chemically defined system using CHIR99021 and TTNPB to generate advanced NSCs (ANSCs). Integrated chromatin accessibility, transcriptomic, and metabolomic analyses revealed molecular mechanisms underlying neural fate commitment. TTNPB synergistically enhanced CHIR99021-mediated neural induction by globally increasing chromatin accessibility and activating neural-specific transcription factors. Compared to NSCs and PSCs, ANSCs exhibited robust upregulation of neural markers and enhanced chromatin remodeling. Metabolomic profiling identified significant metabolic reprogramming during the PSC-to-ANSC transition, with specific enrichment of S-adenosylhomocysteine (SAH), ADP, and glutathione in ANSCs correlating with elevated neural gene expression. Functionally, choline supplementation—regulated via the PEMT pathway—enhanced NESTIN expression and promoted neuroectodermal fate commitment. Our findings establish CHIR99021/TTNPB as a potent synergistic pair for efficient NSC induction and identify choline metabolism as a critical axis governing neuroectodermal lineage specification.

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TTNPB Promotes Pluripotent-to-Neural Stem Cell Transition through Modulating Chromatin Accessibility and Choline Metabolism [RNA-seq]

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mRNA profiles of 50 HB tumors

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