Abstract

Bone marrow mesenchymal stem cells (BMMSCs) facilitate the growth of multiple myeloma (MM) cells, but the underlying mechanisms remain unclear. This study demonstrates that the senescence of MM-MSCs significantly increased, as evidenced by a decrease in proliferation and increase in the number of cells positive for senescence-associated β-galactosidase activity. Senescent MM-MSCs displayed decreased differentiation potential and increased tumor-supporting capacity. Dicer1 knockdown in the MSCs of healthy controls promoted cellular senescence and tumor-supporting capacity, while decreasing the differentiation capacity. Dicer1 overexpression in MM-MSCs reversed the effects on differentiation and reduced cellular senescence. In addition, decreased expression of the microRNA-17 family was identified as a favorable element responsible for increasing senescence, with the expression of p21 increased in Dicer1 knockdown cells. Furthermore, we observed decreased expression of miR-93 and miR-20a in MM-MSCs, while upregulation of miR-93/miR-20a decreased cellular senescence, as evidenced by the increased p21 expression. Importantly, we found that myeloma cells could induce the senescence of MSCs from healthy controls, as observed from the decreased expression of Dicer1 and miR-93/miR-20a and increased expression of p21. Overall, MM cells downregulate Dicer1 in MSCs, which leads to senescence; in turn, senescent MSCs promote MM cell growth, which most likely contributes to disease progression.

Highlights

  • Multiple myeloma (MM) is a malignancy characterized by plasma cell proliferation, initially in the bone marrow microenvironment[1]

  • We studied the senescent features of bone marrow mesenchymal stem cells (BMMSCs) derived from MM patients and explored the biological function of Dicer[1] in the senescence of MMMSCs

  • Senescent features of BMMSCs from patients with MM HC-MSCs were characterized by spindle-like morphology, while MM-MSCs were larger and irregular (Fig. 1a)

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Summary

Introduction

Multiple myeloma (MM) is a malignancy characterized by plasma cell proliferation, initially in the bone marrow microenvironment[1]. This tissue is a complicated network of extracellular matrix and various cells[2]. Increasing body of report suggests that microRNAs (miRNAs) take part in the regulation of MSC senescence[18, 19]. They play an important part in the self-renewal and differentiation of MSCs. As previously indicated, MM-MSCs show a different miRNA profile to that of HC-MSCs, but the roles of these deregulated miRNAs in MM-MSCs are not clearly known[20, 21]. The effect of the Dicer[1] gene on the pathogenesis of MM has not been studied

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