Abstract
IntroductionCell-based therapy represents a new frontier in the treatment of a wide variety of human diseases traditionally associated with morbidity outcomes, including those involving inflammation, autoimmunity, tissue damage, and cancer. However, the use of mesenchymal stem cells (MSCs) to treat multiple myeloma (MM) bone disease has raised concerns. Specifically, evidence has shown that infused MSCs might support tumor growth and metastasis.MethodsIn this study, we used a standard disseminated MM model in mice to identify the in vivo effects of intravenous MSC infusion. In addition, a series of in vitro co-culture assays were preformed to explore whether Fas/Fas ligand (Fas-L) is involved in the inhibitory effects of MSCs on MM cells.ResultsIn the MM mouse model, treatment of MSCs with highly expressed Fas ligand (Fas-Lhigh MSCs) showed remarkable inhibitory effects on MM indenization in terms of extending the mouse survival rate and inhibiting tumor growth, bone resorption in the lumbus and collum femoris, and MM cell metastasis in the lungs and kidneys. In addition, reduced proliferation and increased apoptosis of MM cells was observed when co-cultured with Fas-Lhigh MSCs in vitro. Furthermore, mechanistically, the binding between Fas and Fas-L significantly induced apoptosis in MM cells, as evidenced through an increase in the expression of apoptosis marker and Fas in MM cells. In contrast, Fas-Lnull MSCs promote MM growth.ConclusionsThese data suggest that Fas/Fas-L-induced MM apoptosis plays a crucial role in the MSC-based inhibition of MM growth. Although whether MSCs inhibit or promote cancer growth remains controversial, the levels of Fas-L expression in MSCs determine, at least partially, the effects of MSCs on MM cell growth.
Highlights
Cell-based therapy represents a new frontier in the treatment of a wide variety of human diseases traditionally associated with morbidity outcomes, including those involving inflammation, autoimmunity, tissue damage, and cancer
Effects of Mesenchymal stromal cell (MSC) infusion on multiple myeloma model mice We investigated the 6-week survival rates of mice in each group
The survival rate of MM model mice without MSC or lymphocyte Peyer’s patch adhesion molecules (L-PAM) treatment (MM group) dramatically decreased until all mice died after 6 weeks of feeding
Summary
Cell-based therapy represents a new frontier in the treatment of a wide variety of human diseases traditionally associated with morbidity outcomes, including those involving inflammation, autoimmunity, tissue damage, and cancer. Increased knowledge of the signaling pathways involved in the regulation of osteoblast formation and differentiation from MSCs might provide a better understanding of the pathophysiological mechanisms involved in MM-induced osteoblast inhibition and permit the development of more potential therapeutic agents against bone damage [2,8,9]. In this regard, novel osteoblast-activating agents, such as dickkopf-1-neutralizing antibody [10] and inhibitor of activin A signaling [11], are explored for the clinical treatment of MM bone disease. Additional approaches are urgently needed to achieve systemic bone anabolism and repair large osteolytic lesions
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