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New steps towards the development of artificial lymph nodes

Lymph nodes play a key role in the functioning of our defenses. It is in fact in these small organs that the molecular and protein wastes, collected through the lymphatic system, can signal the presence of an infection or a tumor, and it is always in the lymph nodes that the adaptive immune response is orchestrated - based on antibodies and cells – and it gets able to recognize the threat and defeat it.

Despite their importance, however, we still know little about the cellular origin and development of lymph nodes, a fundamental knowledge for the development of regenerative medicine approaches capable of reconstituting or replacing these organs when they are removed or compromised, as it happens following oncological treatments.

A new research study published in the prestigious journal Immunitycoordinated by Andrea Brendolan of IRCCS Ospedale San Raffaele, in collaboration with Elisa Lenti – reveals for the first time the fundamental steps of this development process. The research was made possible thanks to the support of the AIRC Foundation for Cancer Research.

 

The first experiments with artificial lymph nodes

For over fifteen years Andrea Brendolan's research group has been studying the processes that guide the formation of lymph nodes during embryonic development and reproducing these processes in the laboratory, with the ultimate goal of obtaining real artificial lymph nodes.

To succeed in this ambitious undertaking, it is necessary to understand not only the way in which the different cells that make up the lymph nodes originate and specialize, but the way in which they organize themselves into three-dimensional tissues and structures.

"In biology, the shape and three-dimensional structure of organs are fundamental for their functioning and incredibly complex," says Brendolan, who already in 2019 had reproduced artificial lymph nodes starting from mouse stromal progenitors, grown in the laboratory on a three-dimensional scaffold made of collagen. “Fortunately, stromal progenitors have an extraordinary capacity for self-organization: sometimes it is enough to recreate for them the conditions present in the embryonic or neonatal phase to kick start the development program of the lymph node. That's what we did successfully three years ago."

Using in vivo imaging techniques, the researchers had in fact observed how the new lymph nodes, once transplanted into mice, had connected to the lymphatic system, acquiring morphological and functional characteristics very similar to those of physiological lymph nodes. Very encouraging results in view of a future clinical application: oncological therapies often result in the removal or damage of the lymph nodes and can give rise to secondary lymphedema, a disease of lymph accumulation in the tissues due to the interruption of the lymphatic system.

 

Searching for the ideal cellular source

However, the transition from animals to humans, in addition to requiring further feasibility studies, requires a better understanding of the dynamics of differentiation. Brendolan explains: "In a future clinical context, in which we need to reproduce an artificial human lymph node compatible with the recipient, we cannot resort to the use of progenitor stromal cells, as done in the mouse experiment. This is why it is essential to find a group of stem cells from which to derive more specialized and specific stromal cells, the so-called progenitor cells, which are however still able to fully reproduce a functioning lymph node."

It is precisely with this mission that researchers at San Raffaele studied the differentiation process of the organ: using frontier cellular and genomic techniques, the researchers reconstructed the family tree that connects the great structural cellular variety of the mature lymph node to key progenitors: two in particular, one for the stromal tissues that make up the lymph node, and one for the endothelial tissues.

The discovery of these two cellular progenitors paves the way for the generation of an artificial human lymphoid organ from reprogrammed stem cells, i.e. cells that can be obtained from the patient himself and therefore totally compatible for transplantation.

The result obtained today will take us a step closer to the translational development of our research: a future in which we will not only be able to regenerate the functionality of the lymph nodes if compromised, but in which we will also be able to test in the laboratory, on a realistic model of a human lymph node, the functioning of immunological therapies and the effectiveness of new vaccines.