DNA methylation in AZA+/AZA- mesenchymal stromal cells (MSCs) from patients with chronic myelomonocytic leukemia or healthy individuals
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PROVIDER: PRJNA913799 | ENA |
REPOSITORIES: ENA
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Project description:DNA methylation is a fundamental epigenetic modification regulating gene expression. Aberrant DNA methylation may be involved in the transcriptionally/functionally altered CMML-MSCs. However, understanding the overall DNA methylation profile in MSCs and its changes after the intervention of demethylating drugs such as AZA is still lacking. In this present study, In vitro expanded MSCs from CMML patients (n=10) and healthy individuals (n=5) were treated with AZA or DMSO, and then used for DNA methylation profiling (EPIC) respectively. A total of 30 MSC samples were included. MSCs. Our study reveals that MSCs from different individual cohorts (healthy vs. CMML) exhibit significantly different sensitivity and reactivity to AZA. AZA treatment in vitro modulates aberrant DNA methylation profiles in CMML-MSCs and restores their impaired support for healthy hematopoiesis. Our study shows that the therapeutic effect of AZA on CMML patients is not limited to its inhibitory effect on malignant clones, but also manifested in its regulatory effect on the damaged bone marrow stromal microenvironment. Targeted improvement of bone marrow microenvironment may be a potential way to improve and restore normal hematopoiesis in patients with CMML.
2022-12-22 | GSE221269 | GEO
Project description:This study investigates transcriptomic changes occurring in PDPN+PDGFRa+ stromal cells from murine B16-OVA melanomas (MO5) when ADAM12+ mesenchymal stromal cells (MSCs) are depleted.
2023-10-05 | GSE206794 | GEO
Project description:To characterize and compare XF-iMSC (XenoFree-induced Mesenchymal stem/stromal cells) and various types of MSCs (Adipose-, Bone marrow-, Unbilical cord-derived), we performed a transcriptome analysis of these MSCs
2022-06-22 | GSE206172 | GEO
Project description:Depletion of ADAM12+ MSCs normalizes the tumor stromal microenvironment
| PRJNA852197 | ENA
Project description:Genome wide DNA methylation profiling of normal and pathologic mesenchymal stromal cells (MSCs). The Illumina Infinium 850k Human DNA methylation Beadchip was used to obtain DNA methylation profiles across approximately 850,000 CpGs total DNA from in vitro-amplified MSCs. Samples included 11 normal MSCs, 11 MSCs from MDS patients, and 10 MSCs from AML patients.
2021-12-11 | GSE124390 | GEO
Project description:Human bone marrow mesenchymal stromal cells (MSCs) are conventionally cultured as adherent monolayers on tissue culture plastic. MSCs can also be cultured as 3D cell aggregates (spheroids). Optimised 3D conditions (60,000 MSCs cultured as a spheroid for 5 days) inhibited MSC proliferation and induced cell shrinkage in the absence of cell death. Primary human MSCs isolated from 2 donors were cultured under both monolayer (2D MSCs) and optimised 3D (3D MSCs) conditions. High quality RNA was isolated from all samples, and global gene expression analysis was performed in duplicate (using Agilent SurePrint G3 Human Gene Expression 8x60K v2 Microarrays) to identify gene expression changes in 3D compared to 2D MSC cultures.
2015-09-30 | E-MTAB-3795 | biostudies-arrayexpress
Project description:Comparison of mesenchymal stem/stromal cells (MSCs) between human iPS-derived MSC and human primary cultured MSCs
| PRJNA849564 | ENA
Project description:Bone marrow mesenchymal stromal cells (MSCs) regulate homeostasis and trafficking of cells of the blood lineage. In response to traumatic injury or infection, MSCs are believed to mobilize from the bone marrow, but it is largely unknown how egress into circulation impacts MSC function. Here we show that biomechanical forces associated with trafficking of MSCs from the bone marrow into the vasculature contribute uniquely to genetic signaling that reinforces MSC repression of immune cell activation. Laminar wall shear stress (LSS) typical of fluid frictional forces present on the lumen of arterioles stimulates increases in antioxidant and anti-inflammatory mediators, as well as an array of chemokines capable of immune cell recruitment. Importantly, LSS promotes a signaling cascade through COX2 that elevates prostaglandin E2 (PGE2) biosynthesis, permitting MSCs to suppress immune cell activation in the presence of inflammatory cues. Pharmacological inhibition of COX2 depleted PGE2 and impaired the ability of MSCs to block tumor necrosis factor-α (TNF-α) production, supporting a key role for PGE2 in the MSC immunomodulatory response to LSS. Preconditioning of MSCs by LSS ex vivo was an effective means of enhancing therapeutic efficacy in a rat model of traumatic brain injury, as evidenced by decreased numbers of apoptotic and M1-type activated microglia in the hippocampus and by retention of endogenous MSCs in the bone marrow. We conclude that biomechanical forces provide critical cues to MSCs residing at the vascular interface which influence MSC immunomodulatory and paracrine functions, thus providing unique opportunities for functional enhancement of MSCs used in therapeutic applications.
2017-05-23 | GSE82269 | GEO
Project description:Objectives: Bone marrow (BM) stroma and microenvironmental factors in the BM milieu of myeloid neoplasms are increasingly being recognized as novel perspective therapeutic targets. Lysyl oxidases (LOX/LOXL) are crucial enzymes that cross-link collagen and contribute to the deposition of aberrant stiff extracellular matrix (ECM) in the BM of patients with myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). Here, we studied whether inhibition of LOX/LOXL enzymes produced by BM-derived MSCs favors the differentiation of MDS/MPN hematopoietic stem cell and progenitor cells (HPSCs) and enhances the effects of 5-azacytidine (5-AZA).
Methods: Primary co-cultures of MSCs and HPSCs were established from n=31 MDS/MPN patients and treated with the pan-LOX/LOXL inhibitor PXS-5505, 5-AZA or the combination of both for 4 days. At the end of co-culture, HSPC differentiation was assessed by CFU assays and flow cytometry. In some of the experiments, MSCs monolayers were pre-treated or not with PXS-5505 for 6 days and decellularized using 20 mM ammonia. Subsequently, autologous HSPCs were cultured on ECM matrices in the presence of 5-AZA or PXS-5505 + 5-AZA combination with or without inhibitors of integrin signaling such as blebbistatin, Y-27632 and αvβ3-integrin blocking antibodies. Patient-derived xenografts (PDX) were established in NSG mice based on intrafemoral co-injection of HSPCs and autologous MSCs. PDX were treated with 3 cycles of 5-AZA (75 mg/m2), PXS-5505 (30 mg/kg on alternate days for the duration of 5-AZA treatment) or combination of both.
Results: MSCs of MDS and MPN patients displayed significant overexpression of LOX/LOXL transcripts as compared to healthy age-matched controls. Remarkably, LOX/LOXL inhibition in MSCs/HSPCs co-cultures increased erythroid differentiation of patient HSPCs that had suboptimal or no response to 5-AZA alone. From a total of n=31 advanced stage MDS/MPN patients, n=11 (35.5%) responded to the combination treatment, which was evidenced by a significant increase of CD235a+CD45- erythroid cell production compared to 5-AZA/PXS/untreated arms (p<0.05). Of note, combination treatment with 5-AZA + PXS-5505 facilitated differentiation of CD235+ erythroid progenitors from HSPCs sub-clones with low mutational VAFs. The presence of MSCs was necessary for the effects of the combination treatment and required direct cell contacts between MSCs and HSPCs. Moreover, PXS-5505-mediated alterations of the ECM composition alone were sufficient to induce erythroid
differentiation. Inhibition of integrin-mediated signaling using blebbistatin, Y-27632 and αvβ3-integrin antibodies completely abrogated the effects of PXS-5505 induced erythroid differentiation. In vivo, the combination of PXS-5505 + 5-AZA favored erythroid differentiation of HSPCs and confirmed the in-vitro results. The combination treatment of 5-AZA + PXS-5505 induced the greatest reduction of disease burden as assessed by decrease of spleen indexes, total engraftment rates, BM fibrosis and mutational VAF profiles.
Conclusions: The combination of 5-AZA + LOX/LOXL inhibitor PXS-5505 in MDS and MPN synergistically restores erythropoietic differentiation of primary HSPCs. The effect is dependent of contact interaction between HSPCs and niche components, such as MSCs and MSCs-derived ECM. Our data propose a strong rationale for a BM niche targeted combination treatment with 5-AZA + PXS-5505 in transfusion dependent MDS and MPN, which will be assessed in forthcoming clinical trials.
| EGAS00001006174 | EGA
Project description:We report the gene expression of human chronic myelomonocytic leukemia by performing whole transcriptome shotgun sequencing of peripheral blood mononuclear cells of patients with chronic myelomonocytic leukemia.
2020-08-14 | GSE156209 | GEO