The Forgotten Organ: How the Interstitium Could Revolutionize Medicine
- Rachelle DiMedia
- Sep 8
- 12 min read
The human body has been studied extensively for thousands of years. So, how is it that scientists have only recently begun exploring what they are referring to as an unrecognized organ? What’s even more fascinating is that this organ plays a vital role in many bodily functions and, it turns out, may hold the key to revolutionizing medicine, seeing the human body not as different parts, but as a whole.
The interstitium has long been recognized as an existing entity, but researchers previously overlooked it as unimportant. Now, it is gaining recognition as an essential anatomical structure and a body-wide communication system.
Why is this information only being discovered now? Scientists believed that the interstitum was more solid, not the fluid-filled matrix it actually is. This communication system transports essential material back and forth, connecting all of our organs and tissues into one complex system. It turns out that the reason scientists didn’t know more about this vital body system is because they couldn’t see it.
Previously, when examining fixed slides under a microscope for imaging and analysis, the tissue had to be dehydrated. Since scientists needed to drain all the fluid from these samples, fluid-filled structures would collapse in on themselves. Now, however, a new method is being used in which living tissue can be observed with these spaces filled. Called probe-based confocal laser endomicroscopy (pCLE), it allows experts to take microscopic images of living tissue. Armed with a probe similar to an endoscope, the device has a camera, laser, and specialized sensors.
In 2015, scientists at Beth Israel were examining a patient’s bile duct for signs of cancer, using this method when they noticed tiny fluid-filled structures they didn’t recognize. The tissue was then analyzed by Professor Theise at NYU’s School of Medicine, who biopsied the mysterious structures. However, when he looked at the samples, they had disappeared. Eventually, using the new imaging technology, he realized that the structure had just collapsed when the fluid was removed.2,3
The interstitial space, or the fluid-filled space between cells, has been well-documented, but there has been a paucity of evidence to suggest a similar space between and within tissues. The findings of the Beth Israel scientists and the NYU professor were described as “an unrecognized interstitium in human tissues.”2 The researchers initiated a study, extracting samples from the bile duct, pancreas, and duodenal wall tissues in 12 patients undergoing surgery at Beth Israel, which revealed a unique pattern of spaces between tissues. This was previously identified on imaging, but only the connective tissue was noted.2
Now that they knew what to look for, the scientists went on to identify this tissue nearly everywhere in the body. It is located just below the skin surface, surrounding arteries and veins, and creating fibrous tissue between muscles, as well as the linings of the digestive tract, lungs, and urinary system.2
According to Neil Theise, the medical doctor and NYU professor who identified the interstitium, the collagen it is made of creates a “net” that is found throughout the entire body. It could be the missing link that explains how the human body is composed of an interconnected network of cells, tissues, and organs. It acts as a connection that allows communication through every part of the body, from the “quantum electromagnetic level, all the way up to the cellular level.”5
Theise and his colleagues mapped out the interstitium, organ by organ, and found that the entire body is connected by a network of spaces within and between organs. This discovery creates broad, multidisciplinary links across various scientific and medical fields.
Some scientists are touting the interstitium as the new “organ”, although it hasn’t yet been officially recognized as one yet.1 However, Theise claims that it is not an organ, but a system.2 Either way, the discovery of its importance is paramount in learning about the body and how we might manage multiple diseases in a novel manner that may be a game changer in the field of medicine.
What is the Interstitum?
Previously, the interstitium was thought to be a microscopic, densely packed space between cells, with barrier-like walls of collagen. Scientists believed that your arteries, veins, and the lining of the muscles were connected by this connective tissue. Recently, however, it was discovered that those walls are actually the interstitium, spaces filled with fluid that are only supported by collagen.
Due to advances in imaging and sampling technology, it became apparent that this space is, in fact, a vast, macroscopic anatomical framework. Found within and around tissues, it creates an extensive network of interconnected, fluid-filled sinuses, creating a web that spans the entire body. It provides the structural environment for many cells within the body, and it creates a comprehensive biological matrix that suggests the body is not composed of separate parts, but is, in fact, one whole, cohesive system.
Similar to the skin, the interstitium is often considered one of the largest organs in the body.2
A recent study has shown that the interstitial space is seamless, a labyrinth of living spaces found both within and outside of the organs. The study found that the interstitial space is continuous not only between tissue compartments and fascial planes, but also within the fibrous tissue surrounding blood vessels and nerves that pass through organs. These spaces serve as conduits for interstitial fluid to move in and out, carrying various cells, mediators, and ions that facilitate interactions essential for maintaining homeostasis and overall health. However, it can also be an avenue for toxic substances to spread.
Since it is not a wall of dense connective tissue, but rather a submucosa subjected to directional, peristaltic flow, it presents a potential avenue for the spread of toxic, inflammatory, pro-cancerous, and pro-fibrogenic signaling molecules. This has profound implications for further research into the function and pathology of this space, as well as its potential use in creating improved therapies for multiple illnesses.3
Functions of the Interstitium
1. Communication and defense: The interstitium enables fluids to move efficiently throughout tissues, facilitating the clearance of waste and the distribution of nutrients. Scientists believe this includes the transport of immune cells, making it a key player in the body's defense mechanisms.3
A recent study indicates that this newly identified matrix, which serves as an interface between all systems, is where lymph originates and is eliminated. Lymph collects harmful substances found in cells and tissues that need to be expelled from the body, making it vital for the functioning of your immune cells.3-5 The lymphatic system drains interstitial fluid through capillaries located within the interstitial space. The fluid is then removed from the interstitium and transported to lymphatic vessels, eventually entering the blood circulation through the great veins in the neck.
2. Protection: The interstitium also acts as a shock absorber, creating protection for organs and tissues that expand and contract (i.e., peristalsis in the digestive tract after a meal). It is a honeycomb network of fibrous collagen that can dynamically distend and compress, allowing interstitial fluid to flow through it. It has been found in the lungs, aorta, digestive tract, bladder, and skin, among other places. It is subject to both intrinsic and extrinsic factors, as well as mechanical forces.
3. Volume Control and Interstitial Edema: The interstitium is more than just a structural component—it plays a vital role in fluid dynamics, immune surveillance, and disease progression. The interstitium regulates the body’s fluid volume through hydrostatic pressure (the force exerted by fluid within the blood vessels). These spaces regulate fluid flows, including microvascular filtration, lymph flow, and transserosal flow.
Trans-serosal flow, also known as serosal permeability, refers to the movement of fluid across the serous membranes surrounding the body’s cavities and most internal organs.9 When the hydrostatic pressure within the interstitial space goes up, it reduces how much fluid can pass through the small blood vessels. At the same time, it boosts the movement of fluid across body membranes and into the lymph system. The mutual exchange among the factors influencing these flows determines the interstitial pressure, which, together with these influences, defines the interstitial state of pressure and volume. Factors affecting flows:
● Microvascular pressure
● Lymphatic contractility
● Serosal permeability
4. Blood pressure control: Previously, it was believed that the kidneys were the main organ responsible for regulating total body sodium content and, therefore, controlling blood pressure (BP). Recent literature has shown that, while the kidneys are important in the long-term control of BP, it turns out that the interstitium plays an equally important role. The interstitial space, particularly of the skin, can store large amounts of sodium. Therefore, it is important in total body sodium, water balance, and BP control. Long-term high dietary salt intake leads to an electrical change in the interstitial spaces of the skin, allowing it to act as a reservoir for sodium storage, which in turn increases BP.4
Mechanical and Electrical Signaling in the Interstitium
The interstitium is continuous throughout tissue, in this case, the human pancreas, as well as the entire body. The image on the left shows a cross-section through the draining duct of a human pancreas surrounded by thick bundles of supportive collagen networks in red. On the right, a hyaluronic acid stain in brown demonstrates how the interstitial spaces between the collagen bundles and filaments are filled with hyaluronic acid.” Neil Theise5
The interstitium is a fibrous web of collagen regulated by the mechanical movements of dynamic organs and systems. Movement in one part of the body will affect other areas, creating an efficient grid of mechanical connectivity. The connective fibers forming the structural elements of the interstitial spaces are piezoelectric, meaning they can convert mechanical pressure signals into electrical currents used to transport charged molecules throughout the interstitium. Any mechanical movement of the collagen generates electrical energy, which is crucial in the relationship between interstitial volume and fluid pressure.4,5
Particle movement by flow through the interstitial channels is partially due to mechanical forces:7
● Peristalsis of the gut
● Positional or mechanical pressure on the skin and subcutaneous tissues
● Rhythmic compression of the perivascular/adventitial stroma from arterial wall expansion in systole
● Rhythmically oscillating pressure due to inhalation and exhalation is exerted on the tissues within the thorax and abdomen, like the mesentery
Filtering, Signaling, and Cell Migration
The ubiquitous, uninterrupted pathways created by the interstitium serve as complex, intricate pathways for molecular signaling and cell trafficking. The spaces within the interstitium are filled with hyaluronic acid (HA), which has a high capacity to hold water. It forms a highly charged gel that allows specific molecules to access the interstitium, influencing the movement of both large and small molecules, including cells and other cellular components. Signaling molecules create chemical gradients that guide this movement, which is especially important for understanding cancer, metastasis, fluid balance, edema, and sepsis, among other medical disorders. Theise reported that he actually observed cancer cells moving through these spaces.
” The interstitium is continuous throughout tissue, in this case, the human pancreas, as well as the entire body. The image on the left shows a cross-section through the draining duct of a human pancreas surrounded by thick bundles of supportive collagen networks in red. On the right, a hyaluronic acid stain in brown demonstrates how the interstitial spaces between the collagen bundles and filaments are filled with hyaluronic acid.” Neil Theise5
Medical Implications and Future Research
Understanding how the interstitium works will reveal more of the rules governing the communication between the trillions of cells in the human body, which span vast distances to create the exquisitely complex system that is the human body. Here are a few of the possible ways in which it can be used to find improvements in existing therapies.
Cancer:
One of the most compelling theories is the role of the interstitium in cancer metastasis. The network of submucosal channels throughout the body may serve as a conduit for tumor cells to travel, which may explain the increased risk of metastasis in cancer once it reaches the submucosa. Studies have shown that the initial spread of cancer is largely non-destructive, without significant tissue remodeling; however, malignant cells are able to spread easily through interstitial spaces. The open, fluid-filled spaces allow invasive cancer cells to travel quickly to other parts of the body and into organs. Additionally, the mechanical pressure applied to such spaces (compression on the skin, peristalsis of the GI tract) could further promote spread through these spaces.3
Understanding these pathways will lead to groundbreaking research into early detection and targeted therapies, ultimately leading to the development of new treatment pathways in oncology that may yield better results than previously seen.
Implications for non-malignant disorders:
Edema occurs when the interstitial hydrostatic pressure increases. Edema, the accumulation of fluid in the interstitial space, leads to a number of adverse consequences, depending on the organ system involved:4
Increased distance oxygen must travel to diffuse into tissues
Impairments in lung, heart, and intestinal mechanical and physiological functions
Development of compartment syndrome in organs like the brain, intestines, and kidneys, which cannot expand, causing decreased blood flow and organ failure
Intestinal edema can also prevent surgical wound closure of an open abdomen
Pulmonary edema leads to increased work of breathing and may lead to alveolar flooding
The occurrence and effects of interstitial edema are a result of several factors that are believed to be inflammatory and immune-mediated:10
Increased microvascular (small blood vessels within the body) permeability leading to increased microvascular pressure. Underlying medical reasons that cause increased microvascular pressure include:
Venous insufficiency or obstruction due to clots or compression
Cardiac dysfunction like heart failure
Inflammation
Sepsis.
An increase in fluid or protein filtration resulting from inflammatory processes.
Kidney disease
Liver cirrhosis
Decreased lymphatic system drainage (i.e., after cancer surgery)
Decreased plasma colloid osmotic pressure, which refers to the force exerted by plasma proteins that helps pull water into the bloodstream from surrounding tissues. When this mechanism is impaired, fluid accumulates, leading to edema.
Gravity and immobility: Sitting or standing for long periods causes fluid to pool in lower extremities
High salt (sodium) intake causes the body to retain water
Pregnancy increases fluid volume and pressure on veins
Medications: some BP meds, steroid, and diabetes drugs
New information about the interstitium can help us better understand edema, in the context of “third spacing” in post-operative lymphedema after lymph node removal, as well as anasarca caused by liver, kidney, or heart failure, and duct edema seen in acute large bile duct obstruction conditions.3
Edema and shock: The interstitium is a system that regulates the volume and composition of interstitial fluid, including the modulation of inflammatory processes and the response to shock. Changes in interstitial pressure and volume can occur within minutes, resulting in shifts in the body's salt and water balance, as well as alterations in blood pressure. Hypovolemic shock causes increased gut permeability, allowing digestive enzymes to leak into the interstitial fluid of the intestine. These enzymes, along with inflammatory agents, then enter the general circulation, leading to a systemic inflammatory response syndrome, which can be deadly.4
Infectious disease: The discovery of the interstitium could be crucial for a better understanding of the spread of infectious diseases. Scientists may be able to sample the fluid from within this space to potentially stop the spread and develop a cure.
Immune reactions within the cells of the interstitium may serve as first responders in the spaces they occupy, which has implications for their important roles in non-malignant conditions such as scleroderma, biliary atresia, primary sclerosing cholangitis in the biliary tree, and inflammatory bowel disease.7
Host-microbiome interactions: 7 The interstitium may act as a conduit for pathogens from the microbiome and into systemic circulation. The bidirectional communication between the gut and brain provides the ideal pathway for this interaction, which could explain:
● Necrotizing fasciitis
● The relocation of harmful gut bacteria to the liver, leading to chronic liver disease, fibrosis, cirrhosis, and autoimmune hepatitis
Conclusion:
The auspicious “discovery” of the interstitium as a new organ has ignited interest in its potential influence on various diseases, ranging from autoimmune disorders to age-related conditions. Researchers are investigating whether disruptions in interstitial fluid flow contribute to conditions such as chronic inflammation, tissue degeneration, and fibrosis, as well as arthritis and neurodegenerative diseases, providing insights into these conditions.
Everything from tissue and organ regeneration to GI function will be impacted. The interstitium could even serve as a blueprint for the creation of organ grafts and regenerative medicines.7
Furthermore, medical applications could expand to include the development of new pharmaceutical agents and innovative drug delivery methods. If scientists can harness the fluid dynamics within the interstitium, treatments might be designed to target diseased cells more precisely without causing systemic side effects. Additionally, the interstitium could lead to improvements in imaging technology that may allow doctors to detect early-stage abnormalities, helping to prevent disease progression before symptoms emerge.
Ongoing research is exploring the importance of the interstitium, its relationship to vital anatomy, its biological mechanisms, and its functional role. Humanity may soon benefit from these studies, offering relief and hope to billions of people.
Author: Rachelle DiMedia
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