Fate induction in CD8 chimeric antigen receptor T-cells through asymmetric cell division
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE268878 | GEO | 2024/09/27
REPOSITORIES: GEO
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Project description:Asymmetric partitioning of fate-determinants is a mechanism that contributes to T cell differentiation. However, it remained unclear whether the ability of T cells to divide asymmetrically is influenced by their differentiation state, as well as if enforcing asymmetric cell division rates would have an impact on T cell differentiation and memory formation. Using the murine LCMV infection model, we established a correlation between cell stemness and the ability of CD8+ T cells to undergo asymmetric cell division (ACD). Transient mTOR inhibition proved to increase ACD rates in naïve and memory cells, and to install this ability in exhausted CD8+ T cells. Functionally, enforced ACD correlated with increased memory potential, leading to more efficient recall response and viral control upon acute or chronic LCMV infection. Moreover, transient mTOR inhibition also increased ACD rates in human CD8+ T cells. Transcriptional profiling of first daughter cells, obtained by sorting CD8lo and CD8hi cells after in vitro stimulation, revealed that progenies emerging from enforced ACD exhibited more pronounced early memory signatures, which functionally endowed these cells with strengthened memory features.
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Project description:Human tumors often contain slowly proliferating cancer cells that resist treatment but we do not know precisely how these cells arise. We show that rapidly proliferating cancer cells can divide asymmetrically to produce slowly proliferating “G0-like” progeny that are enriched following chemotherapy in breast cancer patients. Asymmetric cancer cell division results from asymmetric suppression of AKT/PKB kinase signaling in one daughter cell during telophase of mitosis. Moreover, inhibition of AKT signaling with small molecule drugs can induce asymmetric cancer cell division and the production of slow proliferators. Cancer cells therefore appear to continuously flux between symmetric and asymmetric division depending on the precise state of their AKT signaling network. This model may have significant implications for understanding how tumors grow, evade treatment, and recur. 3 replicates each of MCF7 Reactive Oxygen Species (ROS) high, HCT116 ROS high, MCF7 ROS low, and HCT116 ROS low.
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Project description:Asymmetric cell division results in two distinctly fated daughter cells to generate cellular diversity. A major molecular hallmark of an asymmetric division is the unequal partitioning of cell-fate determinant proteins. We have previously established that growth factor signaling promotes protein depalmitoylation to foster polarized protein localization, which in turns drives migration and metastasis. Here, we report protein palmitoylation as a key mechanism for the asymmetric partitioning of the cell-fate determinants Numb (Notch antagonist) and β-catenin (canonical Wnt regulator) through the activity of a depalmitoylating enzyme, APT1. Using point mutants, we show specific palmitoylated residues on proteins, such as Numb, are required for asymmetric localization. Furthermore, by live-cell imaging, we show that reciprocal interactions between APT1 and CDC42 regulate the asymmetric localization of Numb and β-catenin to the plasma membrane. This in turn restricts Notch and Wnt transcriptional activity to one daughter cell. Moreover, we show altering APT1 expression changes the transcriptional signatures to those resembling that of Notch and β-catenin in MDA-MB-231 cells. We also show loss of APT1 depletes the population of CD44+/CD24lo/ALDH+ tumorigenic cells in colony formation assays. Together, the findings of this study demonstrate that palmitoylation, via APT1, is a major mechanism of asymmetric cell division regulating Notch and Wnt-associated protein dynamics, gene expression, and cellular functions.
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Project description:Human tumors often contain slowly proliferating cancer cells that resist treatment but we do not know precisely how these cells arise. We show that rapidly proliferating cancer cells can divide asymmetrically to produce slowly proliferating “G0-like” progeny that are enriched following chemotherapy in breast cancer patients. Asymmetric cancer cell division results from asymmetric suppression of AKT/PKB kinase signaling in one daughter cell during telophase of mitosis. Moreover, inhibition of AKT signaling with small molecule drugs can induce asymmetric cancer cell division and the production of slow proliferators. Cancer cells therefore appear to continuously flux between symmetric and asymmetric division depending on the precise state of their AKT signaling network. This model may have significant implications for understanding how tumors grow, evade treatment, and recur.
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Project description:Wnt signal usually functions as a spatial gradient. A localized Wnt3a can induce asymmetric division of mouse embryonic stem cells, whereas proximal daughter cells maintain self-renew and distal daughter cells acquire hallmarks of differentiation. Here, we develop an approach, SET-seq (same cell epigenome and transcriptome sequencing), to jointly profile epigenome and transcriptome in the same single cell. By utilizing SET-seq, we profile H3K27me3 and H3K4me3 with gene expression in Wnt3a induced asymmetric cell division. H3K27me3, but not H3K4me3, is correlatedly changed with gene expression. Single cells clustered by H3K27me3 recapitulate the clusters defined by gene expression. Furthermore, Aebp2, which is the regulator of H3K27me3, is important for the cell-fate decision with localized Wnt signal. Our results provide a convenient way to jointly profile epigenome and transcriptome in the same cell, and uncover the mechanistic insights into the gene regulatory programs for maintaining and resetting stem cell fate during differentiation.
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Project description:Satellite cells are adult muscle stem cells responsible for muscle regeneration after acute or chronic injuries. The balance between stem cell self-renewal and differentiation impacts the kinetics and efficiency of skeletal muscle regeneration. This study elucidated the function of Islr in satellite cell asymmetric division. Satellite cell specific deletion of Islr compromises muscle regeneration in adult mice by impairing the satellite cell pool. Islr is pivotal for satellite cell proliferation and its deletion promotes asymmetric cell fate segregation of satellite cells. A mechanistic search revealed that Islr interacts and stabilizes the Sparc protein, which activates p-ERK1/2 signaling required for asymmetric division. In combination, the findings have identified Islr as a key regulator of satellite cell asymmetric division through the Sparc/p-ERK1/2 signaling pathway, which provides a new insight into satellite cell biology and open avenues for the treatment of myopathy.
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Project description:Fate induction in CD8 chimeric antigen receptor T-cells through asymmetric cell division
| PRJNA1119378 | ENA
Project description:Hematopoietic stem cells (HSCs) balance self-renewal and differentiation to maintain homeostasis. With aging, the frequency of polar HSCs decreases. Cell polarity in HSCs is controlled by the activity of the small RhoGTPase Cdc42. Here we demonstrate, using a comprehensive set of paired daughter cell analyses that include single cell 3D-confocal imaging, single cell transplants, single cell RNA-seq as well as single cell ATAC-seq, that the outcome of HSC divisions is strongly linked to the polarity status before mitosis, which is in turn determined by the level of the activity Cdc42 in stem cells. Aged apolar HSCs undergo preferentially self-renewing symmetric divisions, resulting in daughter stem cells with reduced regenerative capacity and lymphoid potential, while young polar HSCs undergo preferentially asymmetric divisions. Mathematical modeling in combination with experimental data implies a mechanistic role of the asymmetric sorting of Cdc42 in determining the potential of daughter cells via epigenetic mechanisms. Therefore, molecules that control HSC polarity might serve as modulators of the mode of stem cell division regulating the potential of daughter cells.
2018-12-04 | GSE116708 | GEO
Project description:Hematopoietic stem cells (HSCs) balance self-renewal and differentiation to maintain homeostasis. With aging, the frequency of polar HSCs decreases. Cell polarity in HSCs is controlled by the activity of the small RhoGTPase Cdc42. Here we demonstrate, using a comprehensive set of paired daughter cell analyses that include single cell 3D-confocal imaging, single cell transplants, single cell RNA-seq as well as single cell ATAC-seq, that the outcome of HSC divisions is strongly linked to the polarity status before mitosis, which is in turn determined by the level of the activity Cdc42 in stem cells. Aged apolar HSCs undergo preferentially self-renewing symmetric divisions, resulting in daughter stem cells with reduced regenerative capacity and lymphoid potential, while young polar HSCs undergo preferentially asymmetric divisions. Mathematical modeling in combination with experimental data implies a mechanistic role of the asymmetric sorting of Cdc42 in determining the potential of daughter cells via epigenetic mechanisms. Therefore, molecules that control HSC polarity might serve as modulators of the mode of stem cell division regulating the potential of daughter cells.
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