Yet to Be Charted: Mapping the Lymphatic System Across Body Scales and Expertise Domains

The NHLBI, in conjunction with the Boston Lymphatic Symposium organized an open, virtual workshop (WS) to review the state of the current science and knowledge on the structure and organization of the lymphatic system (LS) and to assess how this knowledge can assist with yet unmet clinical needs. Presentations included latest advances in mapping components of the LS using novel single cell technologies, discovery of lymphatic system-specific biomarkers, new imaging efforts at the clinical level, and introduction of some knowledge management and computational tools available to organize this diverse information.  Presenters and participants were encouraged to highlight remaining challenges and potential opportunities to overcome these challenges. Over 300 participants watched live on the NIH Videocast system (https://videocast.nih.gov/watch=43995)

Background

Many aspects of LS structure, which includes several lymphatic organs connected by the lymphatic vasculature, and function across the body remain poorly understood. The primary roles of the LS are: 1) removal of excess body fluids; 2) absorption and transport of fatty acids/chyle to the circulatory system; 3) blood filtration; 4) mounting the primary defense against infections and cancer through immune cell production and activation; and 5) generation and activation of regulatory immune cells that protect against autoimmune/autoinflammatory disease (1). Building a comprehensive LS map across the body scales (macro-anatomical>meso-tissue>micro-single cell level) will be invaluable to the entire lymphatic research and clinical practice. A lymphatic system map will increase the fundamental understanding of its structure and function, highlight missing information, and generate relevant and novel questions regarding the normal LS structure, organization, function, and transition to lymphatic disease (LD) development. In addition, this fundamental knowledge will enable the clinical management of many LDs, including primary and secondary lymphedema, lymphangiomatosis, lymphatic malformations, Gorham disease, and lipedema, highlighting its broad public health importance.

Goals

Comprehensive mapping of the human LS, from the microscopic to the anatomical/clinical scale is needed to advance the fundamental understanding of LS structure and function, its coordination and interactions with other body tissues and organs, and to provide the basis for new avenues in the clinical management of LS dysfunction in a variety of LDs and many other conditions.  The goals of the workshop included inviting the participants to actively engage in: 1) adding to the current body of information, 2) identifying how various mapping technologies could enable a better understanding of LS in health and disease, and 3) identifying potential research gaps and opportunities.

Summary

The workshop brought together an international group of 13 subject matter experts. The speakers represented various disciplines, including basic science and advanced technologies, such as LS imaging at the clinical and microscopic resolution, including multiplex antibody-based imaging and other novel single cell technologies. Clinical researchers reviewed the state-of-the-science and emphasized the need to fill gaps in knowledge to advance patient care, leading the call to bring together the lymphatic research community for an in-depth understanding of lymphatic vasculature, function, and lymphatic disease development by means of advancing mapping of LS across the entire body.

The ability to obtain and integrate the knowledge about the great diversity of local and shared structures and functions within the distributed LS remains a major challenge. For instance, new LS imaging techniques and genetic biomarkers have been proposed for improving diagnosis of some LD; however, better information about commonality and differences within LS is needed to assess their potential wider applicability. Therefore, updating and augmenting the limited amount of published data using modern approaches, connecting and coordinating diverse research efforts that will help establish knowledge about the basic structure and function of the LS and the pathophysiology of LD is a public health need.

A comprehensive clinical level map of the lymphatic vasculature that connects the components of the LS is not currently available, leaving the lymphatic vasculature as mostly “uncharted territory.” In addition, the interindividual variability of the lymphatic vasculature was brought up as a substantial challenge. The consensus was to begin by mapping the most common patterns observed clinically to help define the normal anatomical lymphatic structures and then to seek to understand which variations may be related to pathological conditions.

Mapping the LS will require state-of-the-art experimental, computational, and knowledge management tools. Some advances in related fields and opportunities already available through existing NIH programs were highlighted. For instance, an effort to organize knowledge about several human organs that has engaged experts from many international consortia is led by the NIH Common Fund Human Biomolecular Atlas Program (HuBMAP) through assembling of the Anatomical Structure Cell Types and Biomarkers (ASCT+B) tables (2,3). The availability of this resource open to the entire research community through the HuBMAP Data Portal and specifically the progress of ASCT+B tables dedicated to some of the human LS organs (bone marrow, thymus, mesenteric lymph nodes, spleen) and the closely related blood vasculature, were brought to the attention of the WS audience to further inform enabling completion of a comprehensive LS knowledge map. The audience was invited to engage in the next steps needed, including providing and organizing information about the lymphatic vasculature through a dedicated ASCT+B table, in addition to creating a standardized nomenclature. Such collaborative opportunities using existing open resources will enable new avenues for lymphatic research and will also attract new investigators with diverse expertise to the field, both likely to strengthen the lymphatic community, science, and clinical practice.

Conclusion

There is an urgent public health need to augment and update the limited amount of scientific research and published literature on the LS through the use of modern approaches. Collaborative approaches integrating basic and clinical research expertise are needed to establish the fundamental knowledge about the structure and function of the normal LS, which will help advance clinical science and management of LS pathophysiology.