ESPE Yearbook of Paediatric Endocrinology

In Brief: Current dogma is that lymphatic vessels are absent in bone and bone marrow. Using advanced 3D-imaging and mouse genetics, these authors show the presence of lymph vessels in bone. Moreover, they show that genotoxic stress causes lymph vessels expansion and lymphangiogenesis in bone, which in turn promotes bone and hematopoietic regeneration.

Commentary: The lymphatic system maintains fluid homeostasis, removes cellular waste products and produces lymphocytes, which are important players in immune defence. Until recently, it was believed that bone, bone marrow and other organs, such as brain and eye, lack lymphatic vessels.

Here, using modified tissue clearing and processing steps and advanced 3D light sheet imaging, these authors uncovered the presence of lymphatic vessels in bone. Immunolabeling and 3D imaging of skeletal tissue is technically challenging due to the calcified nature of bones. Lymphatic vessels, immunolabeled with lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1) and prospero-related homeobox 1 (PROX1), were found across different mouse bones and human bone biopsies, including tibia, femur, sternum, vertebral column, calvarium and hip bones. Irradiation caused proliferation of lymphatic endothelial cells (LECs) expansion of lymphatic vessels. Selective depletion of PROX1+ LECs (PROX1 Cre-iDTA) decreased expansion of lymphatic vessels and reduced numbers of hematopoietic stem cell (HSC) in irradiated bones. Competitive transplantation of bone marrow cells from PROX1 Cre+iDTA mice reduced their reconstituting activity. LECs are known to secrete factors and regulate other cell types. C-X-C motif chemokine 12(CXCL12) was upregulated in LECs after irradiation. Moreover, competitive secondary transplantation of bone marrow cells from LEC specific CXCL12 knockout mice decreased reconstitution ability of HSCs. Radiation injury led to expansion of myosin heavy chain 11 (Myh11) expressing pericyte cells in bones, which contributed to bone regeneration by giving rise to osteoblasts, chondrocytes and adipocytes.

This study establishes the presence of lymphatic vessels in murine and human bones. Further, the study shows that lymphatic vessels are crucial drivers of HSC and bone regeneration following genotoxic injury. Radiation injury caused expansion of lymphatic vessels in bone, promoted lymphangiogenesis and supports hematopoietic and bone regeneration. Taken together, these findings uncover a novel fundamental role of the lymphatic system in skeletal and hematopoietic regeneration post injury and adds to the broad array of its existing physiologic functions.