A proinflammatory response and polarized differentiation of stromal elements characterizes the murine myeloma bone marrow niche.

Abstract

Background: The bone marrow (BM) niche contains non-hematopoietic elements including mesenchymal stromal cells (MSC) and bone marrow endothelial cells (BMEC) which provide mechanical support, and control hematopoietic cell growth and differentiation. Although it is known that multiple myeloma (MM) cells interact closely with the BM microenvironment, little is known about the impact of MM on non-hematopoietic niche-forming cells.

Methods: To address the role of the niche in MM pathogenesis, we utilized the 5TGM1 murine model. During the asymptomatic precursor stage of the model, we isolated the rare non-hematopoietic cells and performed single cell RNA sequencing. Using in-silico methods we characterized the individual cellular components of the niche, their relative abundance and differentiation state before and after exposure to MM cells as well as their intercellular interactions.

Results: MM engraftment increased the abundance of MSC-lineage cells, BMECs and enhanced endothelial to mesenchymal transition. An inflammatory and oxidative stress signal was identified together with polarization of MSC differentiation away from osteocyte formation towards adipocytes which provide growth factors that are known to support MM expansion. BMEC differentiation was polarized towards sinusoidal endothelial cells with a pro-angiogenic/pro-inflammatory phenotype.

Conclusions: MM cells impact the BM niche by generating a pro-inflammatory microenvironment with MSC differentiation being changed to generate cell subsets that favor MM growth and survival. In order to induce remission and improve long-term outcome for MM patients these inflammatory and oxidative stress signals need to be reduced and normal niche differentiation trajectories restored.