Mesenchymal stem cells-macrophages crosstalk and myeloid malignancy

Abstract

As major components of the tumor microenvironment, both mesenchymal stem cells (MSCs) and macrophages can be remodelled and exhibit different phenotypes and functions during tumor initiation and progression. In recent years, increasing evidence has shown that tumor-associated macrophages (TAMs) play a crucial role in the growth, metastasis, and chemotherapy resistance of hematological malignancies, and are associated with poor prognosis. Consequently, TAMs have emerged as promising therapeutic targets. Notably, MSCs exert a profound influence on modulating immune cell functions such as macrophages and granulocytes, thereby playing a crucial role in shaping the immunosuppressive microenvironment surrounding tumors. However, in hematological malignancies, the cellular and molecular mechanisms underlying the interaction between MSCs and macrophages have not been clearly elucidated. In this review, we provide an overview of the role of TAMs in various common hematological malignancies, and discuss the latest advances in understanding the interaction between MSCs and macrophages in disease progression. Additionally, potential therapeutic approaches targeting this relationship are outlined.

Keywords: immunomodulation; leukemia; lymphoma; macrophage; mesenchymal stem cells; myeloma; tumor microenvironment.

Figure 1

Schematic representation of the signals involved in the crosstalk between tumor cells and TAMs in leukemia (A), myeloma (B) and lymphoma (C). Studies have demonstrated the significant impact of macrophages on various crucial pathways involved in the initiation and progression of leukemia, myeloma and lymphoma, including anti-apoptosis and proliferation, immunosuppression, angiogenesis, extramedullary migration, tumor cell homing and drug resistance. Tumor cell can induce a shift in monocyte polarization towards an inhibitory M2-like phenotype (mainly characterized by upregulated CD206 and CD163 expression), thereby promoting their own survival.

Figure 2

Schematic of the potential mechanisms of action mediated by MSCs on macrophages. MSCs can polarize macrophages via direct cell–cell contact or indirectly, such as through soluble factors and extracellular vesicles (including exosomes). In addition, healthy MSCs implantation could induce the activation of Arg-1⁺ macrophages in the bone marrow of ALL mice and repair damaged BMME. TA-MSCs play a crucial role in promoting tumor growth by recruiting monocytes/macrophages. Two distinct subpopulation of MSCs, namely AIF1⁺CSF1R⁺ MSCs and ADAM12⁺PDGFRα⁺ MSCs, respectively promote macrophage recruitment or enhance macrophage phagocytosis, and induce macrophage polarization towards immunosuppressive phenotypes, thereby driving tumor progression.