Lymph Node Organoids Integrate into the Lymphatic System and Restore Function

The lymphatic system is vital to the correct operation of the immune response: lymph nodes are where immune cells communicate with one another in order to direct the response to invading pathogens and other threats. Unfortunately lymph nodes deteriorate with age, becoming inflammatory and fibrotic, no longer able to host the necessary passage and communication of immune cells. Researchers have demonstrated that, at least in late life, this can prevent improvements elsewhere in the aged immune system from producing the expected benefits in the immune response. What use extra immune cells or better immune cells if those cells cannot coordinate correctly? There are signs that lymph node degeneration may be due in part to the presence of senescent cells, in which case we might hope that senolytic therapies will help, but this has yet to be assessed by the research community.

What if new lymph nodes can be provided, however? Today's open access paper is a report on the generation and transplantation of organoids capable of functioning as lymph nodes. In mice, transplanted organoids can integrate with the lymphatic system and begin to perform the duties of lymph nodes. While these were not aged mice, and the transplanted organoids replaced lymph nodes that had been surgically removed, rather than augmenting those damaged by aging, this is still promising. This line of research could become one of the suite of approaches that will needed to restore the immune system of an older individual to full, youthful function.

The other necessary therapies for immune rejuvenation are: regrowth of the thymus, responsible for maturation of T cells of the adaptive immune system, and which atrophies with age; rejuvenation of the hematopoietic stem cell population in the bone marrow, source of all immune cells, and damaged and diminished in older individuals; and clearance of the senescent, exhausted, misconfigured, and otherwise broken or inappropriate immune cells that come to clutter up the immune system in late life. A few different approaches for each of these line items are at various stages of development. Given a the timescale of a decade or two we should be optimistic that the effects of aging on the immune system can be significantly reversed.

Therapeutic Regeneration of Lymphatic and Immune Cell Functions upon Lympho-organoid Transplantation

Lymph node (LN) development is a multistep process involving crosstalk of multiple cell types and culminating in integration of LNs into the lymphatic system. Non-hematopoietic stromal progenitors of lymphoid organs play critical roles in tissue development, organization, and function through the secretion of cytokines, chemokines, and the extracellular matrix (ECM), a tri-dimensional scaffold that provides structural support and anchorage for cells. Afferent-collecting lymphatics transport lymph and antigens to the LN where immune responses are generated. However, surgical resection of LNs, radiation therapy, or infections may damage the lymphatic vasculature and contribute to secondary lymphedema, a chronic disease characterized by excessive tissue swelling, fibrosis, and decreased immune responses.

Currently available lymphedema treatments are limited to manual lymph drainage and compression garments, and definitive therapeutic options are still lacking. Vascularized autologous lymph node transfer (ALNT), a surgical procedure in which a LN flap is harvested and transplanted at the site of resected LNs to improve lymphatic drainage, is emerging as a therapeutic option for the treatment of cancer-associated lymphedema. Although feasible, such an approach requires surgical intervention and can be associated with donor-site complications, which may limit its application.

To circumvent these problems, tissue engineering may provide strategies to develop artificial lymphoid tissues for applications in regenerative medicine. It has been demonstrated that transplantation under the kidney capsule of an engineered stromal cell line expressing lymphotoxin α in a biocompatible scaffold or the delivery of stromal-derived chemokines in hydrogel is sufficient to promote the organization of lymphoid-like structures with immunological function. Whether these approaches contribute to regenerate immune and lymphatic functions in preclinical models of LN resection remains unknown.

Here, we generated lympho-organoids (LOs) using LN stromal progenitors in an ECM-based scaffold and show that LO transplantation at the site of resected LN contributes to restoration of lymphatic and immune functions. Upon transplantation, LOs are integrated into the endogenous lymphatic vasculature and efficiently restore lymphatic drainage and perfusion. Notably, upon immunization, LOs support the activation of antigen-specific immune responses and acquire properties of native lymphoid tissues. These findings provide a robust preclinical approach for the development of synthetic LOs capable of regenerating lymphatic and immune functions.