Mesenchymal stem cells (MSCs) give rise to most bone marrow stromal cells that interact with MM cells. However, the direct involvement of MSCs in MM pathophysiology has not been addressed. In the present study, in vitro and in vivo migration assays reveal that MSCs can migrate towards MM sites, and CCL25 is identified as a major MM cell-produced chemoattractant for MSCs. By in vitro co-culture experiments, we found that MSCs favor the proliferation of stroma-dependent MM cells by secreting soluble factors and cell-cell contact. This growth promoting effect was also demonstrated by intrafemoral co-engraftment experiments in the in vivo mouse myeloma model 5T33MM. We also demonstrated that MSCs protect MM cells in vitro against spontaneous and Bortezomib-induced apoptosis. The tumor-promoting effects of MSCs correlates with their capacity to activate MM cells AKT and ERK activities, accompanied with increased expression of CyclinD2, CDK4 and Bcl-XL, and decreased cleaved caspase-3 and PARP expression. In turn, MM cells upregulate IL-6, IL-10, IGF-1, VEGF and DKK1 expression in MSCs. Finally, systemic infusion of in vitro expanded murine MSCs in 5T33MM mice results in a significantly shorter survival as compared to the control group being injected with MM cells without murine MSCs. MSC infusion is a promising way to support hematopoiesis and control of GVHD for patients after allogeneic hematopoietic stem cell transplantation. However, our data suggest that MSC-based cytotherapy should be considered with caution in MM patients.
- mesenchymal stem cells