Niche-dependent modular regulation of the stem cell transcriptome separates cell identity and potential
Ontology highlight
ABSTRACT:
ORGANISM(S): Drosophila melanogaster
PROVIDER: GSE311622 | GEO | 2026/04/22
REPOSITORIES: GEO
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Project description:The niche controls stem cell self-renewal and progenitor differentiation for maintaining adult tissue homeostasis in various organisms. However, it remains unclear if the niche is compartmentalized to control stem cell self-renewal and stepwise progeny differentiation. In the Drosophila ovary, inner germarial sheath (IGS) cells form a niche for controlling germline stem cell (GSC) progeny differentiation. In this study, we have identified four IGS subpopulations, which form linearly arranged niche compartments for controlling GSC maintenance and multi-step progeny differentiation. Single-cell analysis of the adult ovary has identified four IGS subpopulations (IGS1-4), which identities and cellular locations have been further confirmed by fluorescent in situ hybridization. IGS1 and IGS2 physically interact with GSCs and mitotic cysts to control GSC maintenance and cyst formation, respectively, whereas IGS3 and IGS4 physically interact with 16-cell cysts to regulate meiosis and oocyte development. Finally, one follicle cell progenitor population has also been transcriptionally defined for facilitating future studies on follicle stem cell regulation. Therefore, this study has structurally revealed that the niche is organized into multiple compartments for orchestrating stepwise adult stem cell development, and has also provided useful resources and tools for further functional characterization of the niche in the future.
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Project description:Cellular metabolism is emerging as a potent regulator of cell fate, raising the possibility that the recently discovered metabolic heterogeneity between newly synthesized and chronologically old organelles may impact stem cell fate in mammalian tissues. The small intestine is maintained by actively cycling intestinal stem cells (ISCs) that give rise to metabolically distinct progeny, including their Paneth cell niche. Here, we find that asymmetric cell division generates a subset of ISCs enriched for old mitochondria (ISCmito-O). Although ISCmito-O lack characteristics of reserve stem cells, they form organoids niche-independently, owing to their ability to recreate the Paneth cell niche. Mechanistically, mitochondria in ISCmito-O generate more alpha-ketoglutarate (aKG), driving ten-eleven translocation (Tet) methylcytosine dioxygenase-mediated epigenetic changes that are associated with differentiation towards the Paneth cell fate. aKG supplementation in vivo promotes Paneth cell turnover leading to niche renewal, which promotes recovery from chemotherapy-induced damage in aged animals. Our results reveal a subpopulation of intestinal stem cells whose old mitochondria metabolically regulate cell fate, and provide proof-of-principle for metabolically promoted replacement of specific aged cell types in vivo.
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Project description:Adult tissues with high cellular turnover require a balance between stem cell renewal and differentiation, yet the mechanisms underlying this equilibrium are unclear. The cornea exhibits a polarized lateral flow of progenitors from the peripheral stem cell niche to the center; attributed to differences in cellular fate. To identify genes that are critical for regulating the asymmetric fates of limbal stem cells and their transient amplified progeny in the central cornea, we utilized an in vivo cell cycle reporter to isolate proliferating basal cells across the anterior ocular surface epithelium and perform single-cell transcriptional analysis. This strategy greatly increased the resolution and revealed distinct basal cell identities with unique expression of structural genes and transcription factors. We focused on Sox9; a transcription factor implicated in stem cell regulation across various organs. Sox9 was found to be differentially expressed between limbal stem cells and their central corneal progeny. Lineage tracing analysis confirmed that Sox9 marks long-lived limbal stem cells, which generate progeny that expands centripetally to replenish the cornea. Conditional deletion of Sox9 led to abnormal differentiation and squamous metaplasia in the central cornea, suggesting that it is required for braking cell division symmetry. By inhibiting terminal differentiation of transient amplified progenitors, forcing them into perpetual symmetric divisions, we replicated the Sox9 loss-of-function phenotype. Our findings reveal an essential role for Sox9 in the spatial regulation of asymmetric fate in the corneal epithelium that sustains tissue homeostasis.
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Project description:To study the molecular mechanisms driving dedifferentiation and stem cell plasticity during tissue regeneration, we performed single-cell RNA sequencing at multiple time points-Day 2, Day 5, Day 10, and Day 40,following complete ablation of the limbal stem cell (LSC) population. The primary goal was to characterize the transcriptional reprogramming processes that enable differentiated epithelial cells to reacquire stem cell-like properties and restore the LSC pool. Specifically, we aimed to determine (1) the extent to which dedifferentiated cells recapture native stem cell phenotypes, (2) whether this plasticity is maintained in late differentiated and aged cells, and (3) the niche signals that regulate this process. Our data reveal that differentiated cells undergo extensive transcriptional remodeling, becoming virtually indistinguishable from native LSCs, and functionally sustain long-term tissue homeostasis and repair after repeated injury. Remarkably, this plasticity is retained even in late differentiated and aged cells. Mechanistically, we identify macrophage-derived cytokines as key niche factors promoting dedifferentiation and stemness reacquisition. This dataset provides a comprehensive transcriptional resource of corneal regeneration, offering insights into stem cell plasticity and immune-niche interactions with implications for regenerative medicine and limbal stem cell deficiency therapies.
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Project description:The cell-type-specific function of transcription factors (TFs) is crucial for determining several cellular identities. It is unclear how a single TF can function specifically in different cell types. Here, we define the molecular features that enable OCT4 to reprogram somatic cells into pluripotent or trophoblast stem cells, maintain the self-renewal of embryonic stem (ES) cells, and drive lineage commitment during early embryonic development. Embedded within the intrinsically disordered regions (IDRs) of OCT4, we uncover short linear peptides that are essential for reprogramming (SLiPERs) but dispensable for ES self-renewal. SLiPERs adopt a quasi-ordered state and, during reprogramming, recruit a unique set of proteins to closed chromatin that are unnecessary for ES self-renewal. Interestingly, SLiPERs are not required during early gastrulation but are essential for embryos to develop beyond late gastrulation. Removing SLiPERs leads to aberrant OCT4 binding, derailing the regular transition of ES cells out of pluripotency. Our findings identify modules within IDRs that contribute to the functional versatility and specificity of TFs.
2025-09-30 | PXD067538 | Pride
Project description:The importance of extrinsic regulation of hematopoietic stem cell activity is increasingly acknowledged. Here we report the generation of a new niche system, which supports expansion of mouse hematopoietic stem cells in vitro. Characterization of this niche revealed a transcriptional regulatory network including four critical factors, namely FOS, SPI1, KLF10 and TFEC. Interestingly, these factors are essential for osteoclastogenesis, thus revealing an osteoclastic network that supports hematopoietic stem cell self-renewal. Lentiviral vectors containing putative transcription factors regulating HSC expansion were transfected into GPE cells and gene expression values were compared to empty vector controls.
2013-12-31 | E-GEOD-39835 | biostudies-arrayexpress
Project description:<p>We sought to characterize cellular heterogeneity in the human cerebral cortex at a molecular level during cortical neurogenesis. We captured single cells and generated sequencing libraries using the C1TM Single-Cell Auto Prep System (Fluidigm), the SMARTer Ultra Low RNA Kit (Clontech), and the Nextera XT DNA Sample Preparation Kit (Illumina). We performed unbiased clustering of the single cells and further examined transcriptional variation among cell groups interpreted as radial glia. Within this population, the major sources of variation related to cell cycle progression and the stem cell niche from which radial glia were captured. We found that outer subventricular zone radial glia (oRG cells) preferentially express genes related to extracellular matrix formation, migration, and stemness, including <i>TNC</i>, <i>PTPRZ1</i>, <i>FAM107A</i>, <i>HOPX</i>, and <i>LIFR</i> and related this transcriptional state to the position, morphology, and cell behaviors previously used to classify the cell type. Our results suggest that oRG cells maintain the subventricular niche through local production of growth factors, potentiation of growth factor signals by extracellular matrix proteins, and activation of self-renewal pathways, thereby contributing to the developmental and evolutionary expansion of the human neocortex.</p> <p>For <b>study version 2</b>, we have updated this data set to include additional primary cells that we infer to represent microglia, endothelial cells, and immature astrocytes, as well as additional cells from the developing neural retina, and from iPS-cell derived cerebral organoids. The genes distinguishing these cell populations may reveal biological processes supporting the diverse functions of these cell types as well as vulnerabilities of specific cell types in human genetic diseases and in viral infections.</p> <p>For <b>study version 3</b>, we have updated the data set to include additional primary cells, including those published in Nowakowski, et al., Science 2017: "Spatiotemporal Gene Expression Trajectories Reveal Developmental Hierarchies of the Human Cortex" (<i>in press</i>)</p>
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Project description:Background & Aims: Hierarchical organization of intestine relies on their stem cells by self-renew and producing committed progenitors. Although signals like Wnt are known to animate the continued renewal by maintaining intestinal stem cells (ISCs) activity, molecular mechanisms especially E3 ubiquitin ligases that modulate ISCs ‘stemness’ and supportive niche have not been well understood. Here, we investigated the role of Cullin 4B (Cul4b) in regulating ISC functions. Methods: We generated mice with intestinal epithelial-specific disruption of Cul4b (pVillin-cre; Cul4bfn/Y), inducible disruption of Cul4b (Lgr5-creERT2; Cul4bfn/Y, CAG-creERT2; Cul4bfn/Y) and their control (Cul4bfn/Y). Intestinal tissues were analyzed by histology, immunofluorescence, RNA sequencing and mass spectrum. Intestinal organoids deprived from mice with pVillin-Cre; Cul4bfn/Y, Lgr5-Cre; Cul4bfn/Y, Tg-Cul4b and their controls were used in assays to measure intestinal self-renewal, proliferation and differentiation. Wnt signaling and intestinal markers were analyzed by immunofluorescence and immunoblot assays. Differential proteins upon Cul4b ablation or Cul4b-interacting proteins were identified by mass spectrometry. Results: Cul4b specifically located at ISCs zone. Block of Cul4b impaired intestinal homeostasis maintenance by reduced self-renewal and proliferation. Transcriptome analysis revealed that Cul4b-null intestine lose ISC characterization and showed disturbed ISC niche. Mechanistically, reactivated Wnt pathway could recover intestinal dysfunction of Cul4b knockout mice. Analysis of differential total and ubiquitylated proteins uncovered the novel targeting substrate of Cullin-Ring ubiquitin ligase 4b (CRL4b), immunity-related GTPase family M member 1 (Irgm1) in intestine. Decreased Irgm1 rescued abnormally interferon signaling, overemphasized autophagy and downstream phosphate proteins in Cul4b knockout mice. Conclusion: We conclude that Cul4b is essential for ISC self-renewal and Paneth cell function by targeting Irgm1 and modulating Wnt signaling. Our results demonstrate that Cul4b is a novel ISC stemness and niche regulator.
2022-08-11 | PXD021528 | Pride