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Phosphatidylinositol-3 kinase signaling controls survival and stemness of hematopoietic stem and progenitor cells

ABSTRACT: Phosphatidylinositol-3 kinase signaling controls survival and stemness of hematopoietic stem and progenitor cells

PROVIDER: PRJNA702191 | ENA |

REPOSITORIES: ENA

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Phosphatidylinositol-3 kinase signaling controls survival and stemness of hematopoietic stem and progenitor cells

Project description:Loss of Pten and inhibition of PI3K induced apoptosis of hematopoietic stem/progenitor cells upon endothelial to hematopoietic transition and surviving hematopoietic stem/progenitor cells committed to all blood lineages but displayed reduced stemness

2021-02-17 | GSE166900 | GEO

Phosphatidylinositol-3 kinase signaling controls survival and stemness of hematopoietic stem and progenitor cells.

Project description:Hematopoietic stem and progenitor cells (HSPCs) are multipotent cells giving rise to all blood lineages during life. HSPCs emerge from the ventral wall of the dorsal aorta (VDA) during a specific timespan in embryonic development through endothelial hematopoietic transition (EHT). We investigated the ontogeny of HSPCs in mutant zebrafish embryos lacking functional pten, an important tumor suppressor with a central role in cell signaling. Through in vivo live imaging, we discovered that in pten mutant embryos a proportion of the HSPCs died upon emergence from the VDA, an effect rescued by inhibition of phosphatidylinositol-3 kinase (PI3K). Surprisingly, inhibition of PI3K in wild-type embryos also induced HSPC death. Surviving HSPCs colonized the caudal hematopoietic tissue (CHT) normally and committed to all blood lineages. Single-cell RNA sequencing indicated that inhibition of PI3K enhanced survival of multipotent progenitors, whereas the number of HSPCs with more stem-like properties was reduced. At the end of the definitive wave, loss of Pten caused a shift to more restricted progenitors at the expense of HSPCs. We conclude that PI3K signaling tightly controls HSPCs survival and both up- and downregulation of PI3K signaling reduces stemness of HSPCs.

| S-EPMC8049872 | biostudies-literature

High-dimensional deconstruction of pancreatic cancer identifies tumor microenvironmental and developmental stemness features that predict survival

Project description:Numerous cell states are known to comprise the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME). However, the developmental stemness and co-occurrence of these cell states remain poorly defined. Here, we performed single-cell RNA sequencing (scRNA-seq) on a cohort of treatment-naive PDAC time-of-diagnosis endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) samples (n=25). We then combined these samples with surgical resection (n=6) and publicly available samples to increase statistical power (n=80). Following annotation into 25 distinct cell states, cells were scored for developmental stemness and a customized version of the Ecotyper tool was used to identify communities of co-occurring cell states in bulk RNA-seq samples (n=268). We discovered a tumor microenvironmental community comprised of aggressive basal-like malignant cells, tumor-promoting SPP1+ macrophages, and myofibroblastic cancer-associated fibroblasts associated with especially poor prognosis. We also found a developmental stemness continuum with implications for survival that is present in both malignant cells and cancer-associated fibroblasts (CAFs). We further demonstrated that high-dimensional analyses predictive of survival are feasible using standard-of-care, time-of-diagnosis EUS-FNB specimens. In summary, we identified tumor microenvironmental and developmental stemness characteristics from a high-dimensional gene expression analysis of PDAC using human tissue specimens including time-of-diagnosis EUS-FNB samples. These reveal new connections between tumor microenvironmental composition, CAF and malignant cell stemness, and patient survival that could lead to better upfront risk stratification and more personalized upfront clinical decision-making.

2023-09-06 | GSE242230 | GEO

let-7 controls cancer stemness through ARID3B

Project description:let-7 controls cancer stemness through ARID3B

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Receptor tyrosine kinase signaling promotes post-embryonic morphogenesis and survival of glia and neural progenitor cells

Project description:Receptor tyrosine kinase signaling promotes post-embryonic morphogenesis and survival of glia and neural progenitor cells

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Expression data from Bmi1-null c-Kit+Sca-1+Lineage marker- (KSL) hematopoietic stem/progenitor cells

Project description:Bmi1 is a component of polycomb repressive complex 1 and its role in the inheritance of the stemness of adult somatic stem cells has been well characterized. Bmi1 maintains the self-renewal capacity of adult stem cells, at least partially, by repressing the Ink4a/Arf locus that encodes a cyclin-dependent kinase inhibitor, p16Ink4a, and a tumor suppressor, p19Arf 14. Deletion of both Ink4a and Arf in Bmi1-deficient mice substantially restored the defective self-renewal capacity of HSCs and neural stem cells. Purified KSL cells from BM of wild-type, Bmi1-/-, Ink4a-/-Arf-/-, and Bmi1-/- Ink4a-/-Arf-/- mice were subjected to RNA extraction and hybridization on Affymetrix microarrays.

2011-02-21 | E-GEOD-19796 | biostudies-arrayexpress

Pak2 regulates hematopoietic progenitor cell proliferation, survival, and differentiation.

Project description:p21-Activated kinase 2 (Pak2), a serine/threonine kinase, has been previously shown to be essential for hematopoietic stem cell (HSC) engraftment. However, Pak2 modulation of long-term hematopoiesis and lineage commitment remain unreported. Using a conditional Pak2 knockout mouse model, we found that disruption of Pak2 in HSCs induced profound leukopenia and a mild macrocytic anemia. Although loss of Pak2 in HSCs leads to less efficient short- and long-term competitive hematopoiesis than wild-type cells, it does not affect HSC self-renewal per se. Pak2 disruption decreased the survival and proliferation of multicytokine stimulated immature progenitors. Loss of Pak2 skewed lineage differentiation toward granulocytopoiesis and monocytopoiesis in mice as evidenced by (a) a three- to sixfold increase in the percentage of peripheral blood granulocytes and a significant increase in the percentage of granulocyte-monocyte progenitors in mice transplanted with Pak2-disrupted bone marrow (BM); (b)Pak2-disrupted BM and c-kit(+) cells yielded higher numbers of more mature subsets of granulocyte-monocyte colonies and polymorphonuclear neutrophils, respectively, when cultured in the presence of granulocyte-macrophage colony-stimulating factor. Pak2 disruption resulted, respectively, in decreased and increased gene expression of transcription factors JunB and c-Myc, which may suggest underlying mechanisms by which Pak2 regulates granulocyte-monocyte lineage commitment. Furthermore, Pak2 disruption led to (a) higher percentage of CD4(+) CD8(+) double positive T cells and lower percentages of CD4(+) CD8(-) or CD4(-) CD8(+) single positive T cells in thymus and (b) decreased numbers of mature B cells and increased numbers of Pre-Pro B cells in BM, suggesting defects in lymphopoiesis.

| S-EPMC4409559 | biostudies-literature

KMT9 controls growth and stemness of colorectal cancer

Project description:KMT9 controls growth and stemness of colorectal cancer

| PRJNA632605 | ENA

Phosphatidylinositol 3-Kinase (PI3K) delta blockade increases genomic instability in B cells

Project description:Phosphatidylinositol 3-Kinase (PI3K) delta blockade increases genomic instability in B cells

| PRJNA311552 | ENA