| Bone marrow (BM) microenvironment provides crucial supports to normal and malignant hematopoiesis and several types of cells such as endothelial cells, osteoblasts and mesenchymal stem cells (MSCs) have been shown to contribute to its formation. However, a diverse array of cell types is present in the BM and possibly contributes to the BM microenvironment as well. Macrophages are abundant in the BM and we hypothesized they could be an important player in the normal and malignant hematopoiesis. We first investigated the interactions between MSCs and macrophages and showed that MSCs educate peripheral blood monocytes derived macrophages into a distinct phenotype which has characteristic similar to BM CD14+ monocyte derived macrophages. We also showed, for the first time to our knowledge, that macrophages can induce proliferation of MSCs, implicating a bidirectional interaction between those two types of cells. Next, we show that macrophages and MSCs are capable of inducing proliferation of CD34 positive hematopoietic stem cells and combination of MSCs and macrophages promote differentiation of embryonic stem cells into hematopoietic stem cells, further verifying they can simulate BM microenvironment in vitro. Based on the latter findings, we studied the effect of macrophages and MSCs on multiple myeloma cells, a malignant hematologic condition with exclusive tropism toward BM. Our results show that macrophages and MSCs can support proliferation and survival of myeloma cells independently, with their combination being even superior to either component alone. In conclusion, results from this study provide evidence in strong support of macrophages as an important player in the formation of BM microenvironment in collaboration with MSCs with major implications for investigation of normal and malignant hematopoiesis. |
