Leptin receptor-expressing bone marrow stromal cells are myofibroblasts in primary myelofibrosis

Bone marrow fibrosis is a critical component of primary myelofibrosis (PMF). But the origin of myofibroblasts that drive fibrosis is unknown. Using genetic fate mapping we found that bone marrow Leptin receptor (Lepr) – expressing mesenchymal stromal lineage cells expanded extensively and were the fibrogenic cells in PMF. These stromal cells down-regulated the expression of key haematopoietic stem cell (HSC)- supporting factors and up-regulated genes associated with fibrosis and osteogenesis, indicating fibrogenic conversion. Administration of imatinib or conditional deletion of platelet-derived growth factor receptor a (Pdgfra) from Lepr(+) stromal cells suppressed their expansion and ameliorated bone marrow fibrosis. Conversely, activation of the PDGFRa pathway in bone marrow Lepr(+) cells led to expansion of these cells and extramedullary haematopoiesis, features of PMF. Our data identify Lepr(+) stromal lineage cells as the origin of myofibroblasts in PMF and suggest that targeting PDGFRa signaling could be an effective way to treat bone marrow fibrosis.