Eltrombopag increases the hematopoietic supporting ability of mesenchymal stem/stromal cells

Abstract

Background: Eltrombopag (EP) is a small molecule that acts directly on hematopoietic stem cells (HSCs) and megakaryocytes to stimulate the hematopoietic process. Mesenchymal stem/stromal cells (MSCs) are key hematopoietic niche regulators. Objectives: We aimed to determine whether EP has any effect on MSC function and properties (especially on their hematopoietic-supporting ability) and if so, what changes (e.g. genome-wide transcriptomic alterations) are induced in MSC after EP treatment. Design/Methods: MSCs were isolated from 12 healthy donors and treated with 15 µM and 50 µM of EP for 24 h. The toxicity of the drug on MSCs and their differentiation ability were analyzed, as well as the transcriptomic profile, reactive oxygen species (ROS) and DNA damage and the changes induced in the clonogenic capacity of HSCs. Results: The results show that EP also modifies MSC functions, decreasing their adipogenic differentiation, increasing the expression of genes involved in hypoxia and other pathways related to oxygen homeostasis, and enhancing their ability to support hematopoiesis in vitro. Conclusion: Our findings support the use of EP in cases where hematopoiesis is defective, despite its well-known direct effects on hematopoietic cells. Our findings suggest that further studies on the effects of EP on MSCs from patients with aplastic anemia are warranted.

Altered Expression of microRNAs Implicated in Hematopoietic Dysfunction in the Extracellular Vesicles of Bone Marrow-Mesenchymal Stromal Cells in Aplastic Anemia

“…A total of 57 miRNAs, including precursor and mature miRNAs, were significantly deregulated in AA BM-MSC EVs. These results align with the previous studies, which have reported differential expression of miRNAs in the BM-MSC derived EVs from hematopoietic disorders such as AML 22 , MDS 23,36 , and multiple myeloma 24 . Additionally, the EV miRNA expression profile of our study was in alignment with the BM-MSC exosomal miRNA expression profile as reported by Ferguson et al, 2018 39 .…”

“…Several studies have reported that BM-MSC derived EVs can affect selfrenewal, proliferation, and differentiation of HSPC in normal physiological conditions analogous to that of BM-MSC [19][20][21] . Moreover, in hematological disorders such as acute myeloid leukaemia (AML), myelodysplastic syndrome (MDS) and multiple myeloma (MM), it has been reported that BM-MSC derived EVs can impair the hematopoiesis supportive functions of HSPC [22][23][24] .…”