Engineered lymphatic stroma model applications in central nervous system leukemia

Central nervous system (CNS) involvement frequently occurs in acute lymphoblastic leukemia (ALL), but many questions remain about how leukemia cells access, persist in, and exploit the CNS. The CNS is protected by the meninges, which are fluid filled membranes that surround the brain. Within the meninges, meningeal lymphatic vessels drain cerebrospinal fluid to cervical lymph nodes for immunosurveillance, a potential pathway for leukemia cell migration into or egress from the CNS. Here, we utilize tissue engineered models of the meningeal lymphatics and lymph node stroma to probe how leukemia cells interact with these key tissues. We first demonstrate that standard-of-care chemotherapeutics can damage meningeal lymphatic barriers. Next, we showed that soluble factors from the meningeal lymphatics can support leukemia cell growth while soluble factors from the lymph node model under flow can promote leukemia cell migration. Finally, we show that leukemia cells migrate through the lymph node model under both static and flow conditions. Overall, we have demonstrated the feasibility of using engineered lymphatic models to study leukemia cell behavior in the CNS with the goal of expanding the available experimental platforms for understanding CNS metastasis and relapse. Insight BoxLeukemia commonly infiltrates the central nervous system (CNS), requiring intensive CNS-directed therapies that are often ineffective and cause both acute and long-term toxicities, especially in pediatric patients. The meningeal lymphatics and the deep cervical lymph nodes constitute a pivotal axis in CNS immunity, facilitating drainage of fluid and waste and enabling peripheral immune surveillance in response to CNS-derived signals. Here, we employ in vitro models of the meningeal lymphatics and lymph node stroma to demonstrate their crosstalk in influencing leukemia cell growth and migration. These engineered platforms serve as valuable tools for uncovering mechanistic insights into the meningeal-lymph node axis in the context of CNS-leukemia relapse.