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AA2P-mediated DNA demethylation synergizes with stem cell agonists to promote expansion of stem cells via activation of GAS6/AXL signaling axis [scRNA-Seq]

ABSTRACT: To investigate the graft composition of SCACs expanded and non cultured CD34+ cells

ORGANISM(S): Homo sapiens

PROVIDER: GSE212578 | GEO | 2023/12/18

REPOSITORIES: GEO

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AA2P-mediated DNA demethylation synergizes with stem cell agonists to promote expansion of stem cells via activation of GAS6/AXL signaling axis [bulkRNA-Seq]

Project description:To investigate the transcriptional profile of SCACs, STFL expanded and non-cultured CD34+CD45RA- cells

2023-12-18 | GSE212577 | GEO

AA2P-mediated DNA demethylation synergizes with stem cell agonists to promote expansion of stem cells via activation of GAS6/AXL signaling axis

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-12-18 | GSE212579 | GEO

AA2P-mediated DNA demethylation synergizes with stem cell agonists to promote expansion of hematopoietic stem cells.

Project description:Small molecules have enabled expansion of hematopoietic stem and progenitor cells (HSPCs), but limited knowledge is available on whether these agonists can act synergistically. In this work, we identify a stem cell agonist in AA2P and optimize a series of stem cell agonist cocktails (SCACs) to help promote robust expansion of human HSPCs. We find that SCACs provide strong growth-promoting activities while promoting retention and function of immature HSPC. We show that AA2P-mediated HSPC expansion is driven through DNA demethylation leading to enhanced expression of AXL and GAS6. Further, we demonstrate that GAS6 enhances the serial engraftment activity of HSPCs and show that the GAS6/AXL pathway is critical for robust HSPC expansion.

| S-EPMC10783628 | biostudies-literature

AA2P-mediated DNA demethylation synergizes with stem cell agonists to promote expansion of stem cells via activation of GAS6/AXL signaling axis

Project description:AA2P-mediated DNA demethylation synergizes with stem cell agonists to promote expansion of stem cells via activation of GAS6/AXL signaling axis

| PRJNA876101 | ENA

An engineered Axl 'decoy receptor' effectively silences the Gas6-Axl signaling axis.

Project description:Aberrant signaling through the Axl receptor tyrosine kinase has been associated with a myriad of human diseases, most notably metastatic cancer, identifying Axl and its ligand Gas6 as important therapeutic targets. Using rational and combinatorial approaches, we engineered an Axl 'decoy receptor' that binds Gas6 with high affinity and inhibits its function, offering an alternative approach from drug discovery efforts that directly target Axl. Four mutations within this high-affinity Axl variant caused structural alterations in side chains across the Gas6-Axl binding interface, stabilizing a conformational change on Gas6. When reformatted as an Fc fusion, the engineered decoy receptor bound Gas6 with femtomolar affinity, an 80-fold improvement compared to binding of the wild-type Axl receptor, allowing effective sequestration of Gas6 and specific abrogation of Axl signaling. Moreover, increased Gas6 binding affinity was critical and correlative with the ability of decoy receptors to potently inhibit metastasis and disease progression in vivo.

| S-EPMC4372605 | biostudies-literature

AA2P-mediated DNA demethylation synergizes with stem cell agonists to promote expansion of stem cells via activation of GAS6/AXL signaling axis [scRNA-Seq]

Project description:AA2P-mediated DNA demethylation synergizes with stem cell agonists to promote expansion of stem cells via activation of GAS6/AXL signaling axis [scRNA-Seq]

| PRJNA876108 | ENA

AA2P-mediated DNA demethylation synergizes with stem cell agonists to promote expansion of stem cells via activation of GAS6/AXL signaling axis [bulkRNA-Seq]

Project description:AA2P-mediated DNA demethylation synergizes with stem cell agonists to promote expansion of stem cells via activation of GAS6/AXL signaling axis [bulkRNA-Seq]

| PRJNA876104 | ENA

The actin modulator hMENA regulates GAS6-AXL axis and pro-tumor cancer/stromal cell cooperation

Project description:The dynamic interplay between cancer cells and cancer-associated fibroblasts (CAFs) is regulated by multiple signaling pathways which can lead to cancer progression and therapy resistance. We have previously demonstrated that hMENA, a member of the actin-regulatory protein of Ena/VASP family, and its tissue specific isoforms influence a number of intracellular signaling pathways related to cancer progression. Here, we report a novel function of hMENA/hMENA?v6 isoforms in tumor-promoting CAFs and in the modulation of pro-tumoral cancer cell/CAF crosstalk via GAS6/AXL axis regulation. LC-MS/MS proteomic analysis revealed that CAF over-expressing hMENA?v6 secret the AXL ligand GAS6, favoring the invasiveness of AXL-expressing PDAC and NSCLC cells. Reciprocally, hMENA/hMENA?v6 regulate AXL expression in tumor cells, thus sustaining GAS6-AXL axis, reported as crucial in EMT, immune evasion and drug resistance. Clinically we found that a high hMENA/GAS6/AXL gene expression signature is associated with a poor prognosis in pancreatic (PDAC) and lung cancer (NSCLC) patients. We argue that hMENA contributes to cancer progression through paracrine tumor-stroma crosstalk, with far-reaching novel prognostic and therapeutic implications for tailored therapies in NSCLC and PDAC.

| S-SCDT-EMBOR-2020-50078-T | biostudies-other

Structural basis for Gas6-Axl signalling.

Project description:Receptor tyrosine kinases of the Axl family are activated by the vitamin K-dependent protein Gas6. Axl signalling plays important roles in cancer, spermatogenesis, immunity, and platelet function. The crystal structure at 3.3 A resolution of a minimal human Gas6/Axl complex reveals an assembly of 2:2 stoichiometry, in which the two immunoglobulin-like domains of the Axl ectodomain are crosslinked by the first laminin G-like domain of Gas6, with no direct Axl/Axl or Gas6/Gas6 contacts. There are two distinct Gas6/Axl contacts of very different size, both featuring interactions between edge beta-strands. Structure-based mutagenesis, protein binding assays and receptor activation experiments demonstrate that both the major and minor Gas6 binding sites are required for productive transmembrane signalling. Gas6-mediated Axl dimerisation is likely to occur in two steps, with a high-affinity 1:1 Gas6/Axl complex forming first. Only the minor Gas6 binding site is highly conserved in the other Axl family receptors, Sky/Tyro3 and Mer. Specificity at the major contact is suggested to result from the segregation of charged and apolar residues to opposite faces of the newly formed beta-sheet.

| S-EPMC1356355 | biostudies-literature

Expansion effect of romiplostim on hematopoietic stem and progenitor cells versus other thrombopoietin receptor agonists

Project description:Romiplostim, a thrombopoietin (TPO) receptor agonist, is a clinically approved drug that is clearly effective in reconstituting hematopoiesis in refractory aplastic anemia and　idiopathic thrombocytopenic purpura. However, the mechanism underlying its biological effect is unknown, and its difference with other TPO receptor agonists remains unclear. Therefore, we determined the in vitro expansion effect of romiplostim on human CD34+ hematopoietic stem and progenitor cells (HSPCs) versus recombinant human TPO (rhTPO) and another clinically available drug eltrombopag. We also performed single-cell RNA-seq to define the effect of romiplostim on CD34+ HSPCs at the molecular level. The maximum expansion effect of romiplostim on total CD34+ cells, CD34+CD38+ progenitor cells, and CD34+CD38− immature cells was comparable to that of rhTPO, but higher than that of eltrombopag, particularly on CD34+CD38− immature cells. Single-cell RNA-seq analysis revealed that both romiplostim and eltrombopag induced signatures driven by rhTPO, but romiplostim induced molecular changes related to RHOA signaling at the most primitive subsets in HSPCs that were partially or not driven by eltrombopag. Additionally, romiplostim lacked the ability to induce TFRC expression observed by eltrombopag. In conclusion, romiplostim expands and affects human HSPCs similar to rhTPO but partially different from eltrombopag in terms of induction of gene expression.

2024-09-24 | GSE253936 | GEO

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