A research team from Tokyo University of Science (TUS) has developed a technique to regenerate functional lymph nodes using bioengineered lymphatic tissue. The method, detailed in Nature Communications, involves a centrifugal cell stacking technique to create a three-layered cellular structure named centrifuge-based bioengineered lymphatic tissue (CeLyT). In an animal model, transplantation of CeLyTs restored lymphatic flow, improved lymphedema symptoms, and re-established immune cell populations, offering a potential new therapeutic approach for secondary lymphedema following lymph node removal.
The Challenge of Secondary Lymphedema
The removal of lymph nodes, often necessary during cancer surgeries for staging and preventing disease spread, can lead to secondary lymphedema. This condition, which arises because lymph nodes do not naturally regenerate, is characterized by chronic swelling, discomfort, and reduced mobility in affected regions. Current regenerative medicine strategies, including stem cell and lymphatic tissue transplantation, have demonstrated limited efficacy in improving lymphedema symptoms, and compression therapy primarily delays swelling.
Development of CeLyT
A research team, led by Associate Professor Kosuke Kusamori from the Faculty of Pharmaceutical Sciences at TUS, developed a new lymphatic tissue engineering technique. The study, co-authored by Mr. Shu Obana, Assistant Professor Shoko Itakura, and Professor Makiya Nishikawa, was published in Volume 16 of Nature Communications on November 19, 2025.
Their approach utilizes a centrifugal cell stacking technique to bioengineer replacement tissue. The protocol involves several steps:
- Mesenchymal stem cells (MSCs) are placed in Transwell culture plate wells.
- The plate is centrifuged to form a uniform first layer of MSCs.
- Lymphatic endothelial cells are added, followed by another centrifugation to create a second layer.
- Additional MSCs are introduced with a final centrifugation step, resulting in the three-layered CeLyT structure.
Restoration of Lymphatic Function in Animal Models
The team tested the CeLyT transplantation in a lymphedema animal model where the popliteal and inguinal lymph nodes in the right lower limb of mice had been surgically removed. The transplanted CeLyTs successfully regenerated functional lymph nodes that showed structural similarity to native lymph nodes.
Key findings from the animal study include:
- Restored Lymphatic Flow: CeLyT transplantation re-established lymphatic flow in the affected limbs.
- Symptom Improvement: Mice exhibited a reduction in lymphedema symptoms, with the thickness of their paws and legs returning to normal within a few weeks.
- Immune System Recovery: The mice showed a recovery of filtration capacity and immune cell populations, including T cells and macrophages.
- Reduced Adipose Tissue: Lower accumulation of adipose tissue was observed in the affected areas, reaching levels similar to normal mice.
According to Dr. Kusamori, CeLyTs initially promote lymph and blood vessel formation around the transplantation site. Within several days, an immature lymph node-like structure forms through the incorporation of host-derived cells. This structure then matures and begins to function as a lymph node within 10 days post-transplantation.
Potential Therapeutic and Economic Implications
This study represents the first reported successful regeneration of fully functional lymph nodes through cell transplantation. The researchers suggest that this technique offers a potential therapeutic option for patients who develop lymphedema following oncologic surgeries involving lymph node dissection.
Economically, a single transplantation of CeLyT could provide long-lasting therapeutic benefits. This may lead to reduced cumulative costs associated with repeated hospital visits and the long-term use of compression garments, which are standard treatments for lymphedema.
The study also noted that CeLyTs demonstrated a greater lymphedema-suppressive effect compared to compression therapy and other bioengineered tissues, exhibiting therapeutic effects even in severe chronic lymphedema models. The results indicate that introducing appropriately bioengineered tissue into the lymphatic system may offer an efficacy that surpasses current treatment options for lymphedema.