Leptin Receptor + cells create a perisinusoidal niche for thrombopoiesis in the bone marrow by synthesizing CXCL14

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 bone marrow LepR + cells promote thrombopoiesis by synthesizing the chemokine CXCL14. 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, as well as platelet quality. Megakaryocytes from Lepr-cre; Cxcl14 fl/fl mice expressed lower levels of genes that encode granule proteins as compared to control mice, leading to the release of platelets with fewer α-granules and defective thrombus formation/growth. CXCL14 promoted platelet formation by remodeling lipid metabolism in megakaryocytes, increasing fatty acid transporter expression and enabling megakaryocytes to take up more polyunsaturated fatty acids from circulation. A high fat diet rescued the formation of proplatelet-forming megakaryocytes and platelets, as well as platelet function, 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. Significance To our knowledge, this study presents the first evidence that LepR + stromal cells in the bone marrow regulate terminal differentiation or metabolic function in hematopoietic cells. LepR + cells regulate the maturation of megakaryocytes into proplatelet-forming megakaryocytes and platelet production in the bone marrow as well as platelet quality: platelets produced in the absence of CXCL14 from LepR + cells are depleted of α-granules required for thrombus formation/growth. These findings thus identify a niche for thrombopoiesis in the bone marrow, a mechanism by which LepR + cells regulate thrombopoiesis, and a new function for CXCL14 in the regulation of bone marrow thrombopoiesis.