MESENCHYMAL STEM CELLS SUPPRESS LEUKEMIA VIA MACROPHAGE-MEDIATED BONE MARROW NICHE RESTORATION

Bone marrow mesenchymal stem cells (MSC) play essential roles in supporting hematopoiesis, and dysfunctions of these cells are associated with leukemia. However, whether restoration of the impaired bone marrow (BM) microenvironment can inhibit leukemia remains unknown. Using an established model of mimicking chronic MPN/MDS diseases, we uncovered a deteriorating bone marrow microenvironment associated with the disease development. Intra-bone-marrow instead of systemic transfusion of healthy MSC restored the local bone marrow microenvironment, systemically improved thrombopoiesis and reduced tumor burden, and prolonged survivals in leukemia setting. Mechanistically, the transient donor MSC immediately reprogrammed the leukemia macrophages to fulfill tissue repairing function. Further, transfusion of in vitro MSC-reprogrammed macrophages largely recapitulated the microenvironment restoration and therapeutic effects of MSC. Our study reveals the pivotal role of resident macrophages for MSC-mediated microenvironment restoration and therapeutic effects in a chronic leukemia setting, which provides insights into translational application of MSC in MDS/MPN leukemia patients.