Downregulation of MMP1 in MDS-derived mesenchymal stromal cells reduces the capacity to restrict MDS cell proliferation

Sida Zhao,Xiao Li,Youshan Zhao,Qingqing Zheng,Chengming Fei,Chunkang Chang,Juan Guo

doi:10.1038/srep43849

Abstract

The role of mesenchymal stromal cells (MSCs) in the pathogenesis of myelodysplastic syndromes (MDS) has been increasingly addressed, but has yet to be clearly elucidated. In this investigation, we found that MDS cells proliferated to a greater extent on MDS-derived MSCs compared to normal MSCs. Matrix metalloproteinase 1(MMP1), which was downregulated in MDS-MSCs, was identified as an inhibitory factor of MDS cell proliferation, given that treatment with an MMP1 inhibitor or knock-down of MMP1 in normal MSCs resulted in increased MDS cell proliferation. Further investigations indicated that MMP1 induced apoptosis of MDS cells by interacting with PAR1 and further activating the p38 MAPK pathway. Inhibition of either PAR1 or p38 MAPK can reverse the apoptosis-inducing effect of MMP1. Taken together, these data indicate that downregulation of MMP1 in MSCs of MDS patients may contribute to the reduced capacity of MSCs to restrict MDS cell proliferation, which may account for the malignant proliferation of MDS cells.

Highlights

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal disorders derived from hematopoietic stem and progenitor cells(HSPC), and is characterized by ineffective bone marrow haematopoiesis, peripheral blood cytopaenias and a risk of progression to acute myeloid leukaemia[1]
myelodysplastic syndromes (MDS) cells proliferate to a greater extent on MDS-mesenchymal stromal cells (MSCs) compared with normal control MSCs
The matrix metalloproteinase 1 (MMP1) protein levels were decreased in MDS-derived MSCs, which is consistent with MMP1 mRNA expression (Fig. 2b)

Summary

Introduction

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal disorders derived from hematopoietic stem and progenitor cells(HSPC), and is characterized by ineffective bone marrow haematopoiesis, peripheral blood cytopaenias and a risk of progression to acute myeloid leukaemia[1]. Mesenchymal stromal cells (MSCs) are key components of the BM microenvironment and play a crucial role in supporting and regulating HSPC6,7. In addition to their supportive effects, stromal cells may facilitate apoptosis of hematopoietic cells in some pathological circumstances[8,9]. The role of MMP1 in the interaction of MSCs and MDS cells was evaluated. MMP1 secreted from MSCs inhibits the growth and induces apoptosis of SKM-1cells and primary CD34 +cells from MDS patients through interaction with PAR1, which further activates p38 MAPK and downstream genes. Downregulation of MMP1 in MDS-derived MSCs is associated with increased MDS cell proliferation

Methods

Results

Conclusion