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

Bone marrow fibrosis is a critical component of primary myelofibrosis (PMF). However, the origin of the 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 downregulated the expression of key haematopoietic-stem-cell-supporting factors and upregulated 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 signalling could be an effective way to treat bone marrow fibrosis.