Inflammatory Bone Marrow Mesenchymal Stem Cells in Multiple Myeloma: Transcriptional Signature and In Vitro Modeling

SIMPLE SUMMARY: Multiple myeloma cells mainly proliferate in the bone marrow (BM). Mesenchymal stem cells (MSCs) in the BM of MM patients are tumor supportive and exhibit an inflammatory transcription signature and contribute to drug resistance. Due to their rarity in the BM, downstream functional characterization of the cells requires in vitro expansion. We conducted a systemic analysis of public expression data and reported the loss of the inflammatory signature during in vitro expansion. However, further analysis on additional publicly available expression data revealed that cytokine stimulations and coculture with immune cells or cancer cells were able to reactivate the transcription signature. Our findings established a crucial foundation for future research into the contribution of the inflammatory status to the tumor-supportive functions of BM MSCs in disease progression and resistance to therapy. ABSTRACT: Bone marrow mesenchymal stem cells (BM MSCs) play a tumor-supportive role in promoting drug resistance and disease relapse in multiple myeloma (MM). Recent studies have discovered a sub-population of MSCs, known as inflammatory MSCs (iMSCs), exclusive to the MM BM microenvironment and implicated in drug resistance. Through a sophisticated analysis of public expression data from unexpanded BM MSCs, we uncovered a positive association between iMSC signature expression and minimal residual disease. While in vitro expansion generally results in the loss of the iMSC signature, our meta-analysis of additional public expression data demonstrated that cytokine stimulation, including IL1-β and TNF-α, as well as immune cells such as neutrophils, macrophages, and MM cells, can reactivate the signature expression of iMSCs to varying extents. These findings underscore the importance and potential utility of cytokine stimulation in mimicking the gene expression signature of early passage of iMSCs for functional characterizations of their tumor-supportive roles in MM.