Vanishing Act: Lymphatic Vessels and Disappearing Bones

Generalized lymphatic anomaly (GLA) and Gorham-Stout disease (GSD) are related diseases of the lymphatic system. Patients with GLA or GSD develop ectopic lymphatic vessels in bone and gradually lose bone. Despite growing interest in the development of tissue-specific lymphatics, the cellular origin of bone lymphatic endothelial cells (bLECs) is not known, and the development of bone lymphatics has not been fully characterized. In this dissertation, I review the latest advances in research on the development of the lymphatic system and human lymphatic diseases. I also present my work on the development of bone lymphatics in mouse models of GLA and GSD. I show by lineage-tracing that bLECs arise from pre-existing Prox1-positive LECs. I demonstrate that bone lymphatics develop in a stepwise manner, where regional lymphatics grow, breach the periosteum, and then invade bone. I also show that osteoclasts are closely associated with invading lymphatics and that lymphatic invasion of bone is impaired in mice that lack osteoclasts. Additionally, I demonstrate that rapamycin suppresses the formation of bone lymphatics in mouse models of GLA and GSD. These findings shed light on the development of bone lymphatics, a process that has puzzled investigators since Gorham and Stout published their landmark paper over 60 years ago. They also show that an emerging treatment for GLA and GSD patients can inhibit lymphatic invasion of bone.