Highways Hidden in Plain Sight

In 2018, researchers announced the discovery of the interstitium, a previously overlooked anatomical structure that permeates tissues throughout our bodies and those of other vertebrates. The interstitium was long mischaracterized by pathologists as dense connective tissue because its hollow structures collapse during traditional tissue fixation. Dr. Neil Theise and his team at New York University School of Medicine revealed the natural anatomical structure and function across various tissue types using a novel live imaging technique, probe-based confocal laser endomicroscopy (pCLE). This groundbreaking discovery transforms our understanding of tissue organization, fluid transport, and cellular motility throughout the human body.

The interstitium acts as a dynamic highway for fluid exchange, enabling motile cells such as immune cells to traverse tissues. Previously, the prevailing view was that cells moved rapidly through blood vessels but navigated through tissue slowly by remodeling and squeezing through dense extracellular matrices. While this remains true to some extent, the interstitium offers a complementary system of transportation, facilitating rapid movement and improved access to cells within tissues. This revelation reshapes our understanding of how cells, including motile immune cells, navigate the body and how humoral signals are transported through tissues.

This paradigm shift also applies to cancer metastasis, a process heavily studied for its reliance on epithelial-mesenchymal transition (EMT). EMT enables cancer cells to break through barriers, remodel tissue, and migrate to distant organs. While EMT explains much of this behavior, the discovery of the interstitium suggests that cancer cells may exploit these fluid pathways to metastasize and migrate to secondary tissue sites more efficiently. Indeed, research from 2021 provided evidence that cancer cells use the interstitium as a transportation network. This insight challenges long-standing paradigms of how cancer spreads, prompting scientists to revisit decades of assumptions about tumor migration and tissue invasion.

Equally important is the impact of this discovery on molecular medicine aimed at fighting cancer and other diseases. Many modern therapies—such as therapeutic monoclonal antibodies (MAbs) and cellular therapies—are designed to target diseased tissues. However, how these treatments traverse the body and penetrate tissues with varying levels of efficiency remains unclear. Understanding the interstitium may reveal new mechanisms by which these therapies navigate tissue environments and guide the development of more effective treatments optimized for delivery to specific cell types.

More broadly, the interstitium provides a fresh perspective on cellular biology, particularly in immunology. As a site of fluid transfer and cellular interaction, it likely plays a critical role in immune surveillance and tissue homeostasis. Characterizing the cells and molecules within the interstitium will likely clarify its role and reveal how its unique microenvironment influences cellular differentiation into various subtypes, offering new insights into immune cell classification, inflammation resolution (or persistence), and disease progression. 

The discovery of the interstitium is not merely a footnote in anatomical history; it offers crucial insights into how systemic signals are transmitted and how the immune system operates as a distributed organ system. Much like blood platelets—once dismissed as mere debris but now known to be essential for blood clotting—the interstitium remained hidden in plain sight until it was examined with the right microscope and experimental approach. By exploring the biology of this vast and dynamic system, scientists stand to unlock transformative insights that will reshape medicine in the years to come.