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Human Mesenchymal Stem / Stromal Cells (hMSCs) treated with Eltrombopag show increase of the hematopoietic supporting ability

ABSTRACT: Eltrombopag (EP) is a small molecule that acts on hematopoietic cells and megakaryocytes to stimulate the hematopoiesis. Mesenchymal stem/stromal cells (MSCs) are key hematopoietic niche regulators. In the current work we aimed to assess if EP exert any effect on MSCs function, especially on their hematopoietic-supporting ability, and if so, what are the changes (including transcriptomic) induced in MSCs after EP treatment. For this purpose, MSCs were isolated from 12 healthy donors and treated with 15 uM and 50 uM of EP for 24 hours. The toxicity of the drug on MSCs and their differentiation ability were analyzed, as well as the transcriptomic profile, ROS and DNA damage and finally the changes induced in the clonogenic capacity of HSC. We observed that EP acts on MSCs decreasing their adipogenic differentiation, increasing the expression of genes involved in hypoxia and other pathways and enhancing their ability to support hematopoiesis. We used high density oligo microarrays (Affymetrix Clariom_S_Human) to obtain the global programme of gene expression underlying the effect of the Eltrombopag (EP) and Thrombopoietin (TPO) in human MSCs (derived from bone marrow) and identify the genes activity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE202127 | GEO | 2023/01/07

REPOSITORIES: GEO

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Project description:Ineffective hematopoiesis is a hallmark of myelodysplastic syndromes (MDS). Hematopoietic alterations in MDS patients strictly correlate with microenvironment dysfunctions, eventually affecting also the mesenchymal stromal cells (MSCs) compartment. Stromal cells are indeed epigenetically reprogrammed to cooperate with leukemic cells and propagate the disease as "tumor unit"; therefore, changes on MSCs epigenetic profile might contribute to the hematopoietic perturbations typical of MDS. Here, we unveil that the histone variant macroH2A1 (mH2A1) regulates the crosstalk between epigenetics and inflammation in MDS-MSCs, potentially affecting their hematopoietic support ability. We show that the mH2A1 splicing isoform mH2A1.1 accumulates in MDS-MSCs, correlating with the expression of the Toll-like receptor 4 (TLR4), an important pro-tumor activator of MSC phenotype associated to a pro-inflammatory behavior. MH2A1.1-TLR4 axis was further investigated in HS-5 stromal cells after ectopic mH2A1.1 overexpression (mH2A1.1-OE). Proteomic data confirmed the activation of a pro-inflammatory signature associated to TLR4 and nuclear factor kappa B (NFkB) activation. Moreover, mH2A1.1-OE proteomic profile identified several upregulated proteins associated to DNA and histones hypermethylation, including S-adenosylhomocysteine hydrolase, a strong inhibitor of DNA methyltransferase and of the methyl donor S-adenosyl-methionine (SAM). HPLC analysis confirmed higher SAM/SAH ratio along with a metabolic reprogramming. Interestingly, an increased LDHA nuclear localization was detected both in mH2A1.1-OE cells and MDS-MSCs, probably depending on MSC inflammatory phenotype. Finally, coculturing healthy mH2A1-OE MSCs with CD34+ cells, we found a significant reduction in the number of CD34+ cells, which was reflected in a decreased number of colony forming units (CFU -Cs). These results suggest a key role of mH2A1.1 in driving the crosstalk between epigenetic signaling, inflammation and cell metabolism networks in MDS-MSCs.

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Human Mesenchymal Stem / Stromal Cells (hMSCs) treated with Eltrombopag show increase of the hematopoietic supporting ability

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