The rising incidence of cancer worldwide has led to an increasing number of surgeries that involve the removal of lymph nodes.

Although these procedures play a major role in cancer staging and preventing the spread of malignancies, they sometimes come with severe long-term consequences.

Since lymph nodes do not naturally regenerate once removed, their absence can lead to a condition known as secondary lymphoedema.

It manifests as chronic swelling, discomfort, and reduced mobility in affected limbs or regions, severely affecting a patient’s quality of life.

Consequently, a major focus within the field of regenerative medicine is the development of strategies to restore or regenerate damaged lymphatic structures to effectively treat secondary lymphoedema.

Existing approaches have largely centred on stem cells and lymphatic tissue transplantation.

However, these techniques often require complex preparation protocols and, more importantly, have demonstrated limited efficacy in improving the key clinical symptoms of lymphoedema.

Against this backdrop, a research team led by Associate Professor Kosuke Kusamori from the Faculty of  Pharmaceutical Sciences at Tokyo University of Science (TUS), Japan, is pioneering an innovative technique for lymphatic tissue engineering that could revolutionise the treatment of secondary lymphedema.

Their study, published in the journal Nature Communications, describes a straightforward protocol to produce bioengineered lymphatic tissues that can restore lymphatic flow after the removal of lymph nodes.

This work was co-authored by second-year doctoral student Mr. Shu Obana, Assistant Professor Shoko Itakura, and Professor Makiya Nishikawa, also from TUS.

The proposed approach is based on a novel centrifugal cell stacking technique to bioengineer replacement tissue for surgically removed lymph nodes.

First, the researchers placed mesenchymal stem cells (MSCs), which are known to support tissue regeneration and provide structural scaffolding, in the wells of a Transwell culture plate.

By centrifuging the entire plate, MSCs settled down uniformly at the bottom of the wells, forming a first layer.

Then, the researchers added lymphatic endothelial cells to the wells, followed by another round of centrifugation to spread them evenly as a second layer.

Finally, following a final centrifugation step after adding MSCs again, the result was a three-layered cellular structure, which the researchers called centrifuge-based bioengineered lymphatic tissue (CeLyT).

Using a lymphoedema animal model, the team regenerated functional lymph node that exhibited structural similarity with native lymph node.

They confirmed that transplanting CeLyTs restored lymphatic flow in mice whose poplitaeal and inguinal lymph nodes in the right lower limb had been removed.

As a result, these mice exhibited remarkable improvement in lymphoedema symptoms, with the thickness of their paws and legs returning to normal within a few weeks.

Additionally, mice that received CeLyTs also showed recovery of filtration capacity and immune cell populations such as T cells and macrophages, and lower accumulation of adipose tissue in affected areas, reaching levels similar to normal mice.

The researchers carefully analysed the structures that formed after CeLyT transplantation to shed light on the observed therapeutic effects.

“CeLyTs may initially induce lymph and blood vessel formation around the transplantation site, leading to the establishment of an immature lymph node-like structure formed by incorporating host-derived cells into the tissue within several days, followed by its maturation and ability to function as a lymph node within 10 days after transplantation,” explains Dr. Kusamori.

This study marks the world’s first successful regeneration of fully functional lymph nodes through cell transplantation, offering a promising therapeutic option for patients who develop lymphoedema, following oncologic surgeries involving lymph node dissection.

Economically, a single transplantation could provide long-lasting therapeutic benefits, substantially reducing the cumulative costs associated with repeated hospital visits and long-term use of compression garments.

Overall, these results highlight the strong curative potential of introducing appropriately bioengineered tissue into the lymphatic system, surpassing the efficacy of current treatment options for lymphoedema.

“Although compression therapy represents the gold standard for the treatment of lymphoedema in clinical practice, it usually delays the swelling in the paws of lymphoedema mice. By contrast, CeLyTs were more effective at suppressing lymphoedema, also exhibiting strong therapeutic effects even in a more severe chronic lymphoedema model,” remarks Dr. Kusamori.

“Moreover, CeLyTs demonstrated a greater lymphoedema-suppressive effect, compared with bioengineered tissues fabricated by other tissue engineering methods.”

Let’s hope for CeLyTs to be translated into clinical practice!

Source: Tokyo University of Science