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Identification of dormant cells using a novel fluorescent reporter of RNA-polymerase II activity

ABSTRACT: Dormancy is a reversible cellular state in which the cell cycle and metabolic activity of a cell is dramatically decreased, leading to protection from genetic damage and prolonged survival. One example of dormant cells is the somatic stem cell, which is crucial for tissue homeostasis and response to injury or transplantation. However, while dormant cells have been well characterized in some tissues, the ability to identify them irrespective of tissue of origin remains elusive. Moreover, in some tissues (e.g. the intestinal epithelium) dormant stem cells showed heterogeneity in the marker’s profile that makes their identification and isolation challenging. Here, we developed a live cell reporter of dormancy based on our observation that phosphorylation of RNA Polymerase II (RNApII), a hallmark of active mRNA transcription elongation, is largely absent in dormant stem cells from multiple lineages. We show that insertion of a short RNApII kinase target peptide directly into the yellow fluorescent protein Venus generates a live cell Optical Stem Cell Activity Reporter (OSCAR) for detection of dormant cells. We found, using small intestinal crypt cultures, that OSCAR is able to show the dynamics of dormancy induction and cellular differentiation in real time. Generation and analysis of mice ubiquitously expressing OSCAR showed several populations of OSCARhigh and OSCARlow cells. Microscopy, RNA-Seq and single-cell culture confirmed that OSCAR enables direct identification and isolation of cell populations bearing different transcriptional states and provides a useful tool for understanding dormant cell biology.

ORGANISM(S): Mus musculus

PROVIDER: GSE147030 | GEO | 2021/04/16

REPOSITORIES: GEO

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Hematopoietic stem cells (HSCs)

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RNA-sequencing of D2A1 and D2.OR cell lines in both 2D and 3D cultures

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Proteomic Insight into Early Establishment of Seed Dormancy in Xanthium Strumarium

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2024-08-22 | PXD052504 | Pride

Modeling androgen deprivation therapy-induced prostate cancer dormancy and its clinical implications

Project description:Purpose: Treatment-induced tumor dormancy is a state in cancer progression where residual disease is present but remains asymptomatic. Dormant cancer cells are treatment-resistant and responsible for cancer recurrence and metastasis. Prostate cancer (PCa) treated with androgen-deprivation therapy (ADT) often enters a dormant state. ADT-induced PCa dormancy remains poorly understood due to the challenge in acquiring clinical dormant PCa cells and the lack of representative models. We, therefore, aimed to develop clinically relevant models that can be used for studying ADT-induced PCa dormancy. Experimental design: Dormant PCa models were established by castrating mice bearing PCa patient-derived xenografts (PDXs) of hormonal naïve or sensitive PCa. Dormancy status and tumor relapse were monitored and evaluated. Paired pre- and post-castration (dormant) PDX tissues were subjected to morphological and transcriptome profiling analyses. Results: We established eleven ADT-induced dormant PCa models that closely mimicked the clinical courses of ADT-treated PCa. We identified two ADT-induced dormancy subtypes that differed in morphology, gene expression, and relapse rates. We discovered transcriptomic differences in pre-castration PDXs that predisposed the dormancy response to ADT. We further developed a dormancy subtype-based, predisposed gene signature that was significantly associated with ADT response in hormonal naïve PCa and clinical outcome in castration-resistant PCa treated with ADT or androgen-receptor pathway inhibitors.

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Project description:Quiescent hematopoietic stem cells (HSCs) are typically dormant, and only a few quiescent HSCs are active. The relationship between “dormant” and “active” HSCs remains unresolved. Here we generated a G0 marker (G0M) mouse line that visualizes quiescent cells. G0M identifies a small population of active HSCs (G0Mlow), which are distinct from dormant HSCs (G0Mhigh), within the conventional quiescent HSC fraction. Single-cell RNA-Seq analyses showed that the gene expression profiles of these populations were nearly identical, yet differed in their Cdk4/6 activity. Furthermore high-throughput small molecule screening revealed that high concentrations of cytoplasmic calcium ([Ca2+]c) were linked to dormancy of HSCs. These findings indicate that G0M separates dormant and active adult HSCs, which are regulated by Cdk4/6 and [Ca2+]c. This G0M mouse line represents a useful resource for investigating physiologically important stem cell subpopulations.

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