Abstract
Leptin Receptor-expressing (LepR (+) ) stromal cells in the bone marrow are a critical source of growth factors for the maintenance of hematopoietic stem cells (HSCs) and most restricted hematopoietic progenitors. An important unresolved question is whether they also regulate terminal differentiation in some hematopoietic cells. We found that LepR (+) cells promote thrombopoiesis by synthesizing the chemokine CXCL14, which is expressed in the bone marrow by a subset of LepR (+) cells. Cxcl14 -expressing LepR (+) cells extend fine processes that wrap around perisinusoidal megakaryocytes. Deletion of Cxcl14 from LepR (+) cells did not significantly alter HSC function or most aspects of bone marrow hematopoiesis, including megakaryocyte generation; however, it significantly reduced the numbers of proplatelet-forming megakaryocytes in the bone marrow and platelets in the blood. CXCL14 promoted platelet formation by remodeling lipid metabolism in megakaryocytes, increasing fatty acid transporter expression and enabling megakaryocytes to use more polyunsaturated fatty acids from the circulation. A high fat diet rescued the formation of proplatelet-forming megakaryocyte and platelets in Lepr-cre; Cxcl14 (fl/fl) mice. CXCL14 protein was sufficient to promote platelet formation by megakaryocytes in vitro and in vivo. LepR (+) cells thus create a perisinusoidal niche for thrombopoiesis by producing CXCL14, which regulates lipid metabolism and terminal differentiation in megakaryocytes. KEY POINTS: Leptin Receptor (+) stromal cells regulate terminal differentiation in megakaryocytes in addition to maintaining stem and progenitor cells CXCL14 from Leptin Receptor (+) cells promotes the formation of platelets by remodeling lipid metabolism in megakaryocytes in the bone marrow.