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Meet Your New Organ — the Interstitium

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The interstitium might be the reason some complementary-medicine techniques, such as acupuncture and myofascial-release therapy, work, says one researcher.

Scientists have discovered what they believe is a new organ in our bodies — one that’s important to cell communication, and perhaps the spread of diseases like cancer. And it’s so big that it was easy to miss … until now.

The interstitium is a body-wide web of fluid-filled spaces residing beneath the top layer of skin and surrounding muscles, blood vessels, fascia, the gut, and other organs, the researchers state in the journal Scientific Reports.

The compartments likely serve as dynamic “shock absorbers” to protect other body components.

The organ also provides a “highway of moving fluid,” the scientists explain. By moving fluid through the network via peristalsis, it could play a key role in cell signaling and inflammation. The network is also the source of lymph, the fluid key to the immune system.

This latticework may play a role in the workings of techniques like acupuncture and myofascial release therapy. It may also be the conduit for injurious agents in the body, such as spreading tumor cells and allowing cancer to metastasize — a process that’s remained a mystery, says the study’s co-lead author Neil Theise, MD, a pathologist and professor at the New York University School of Medicine.

The interstitium was hiding in plain sight because the usual way of preparing microscope slides involved draining fluid, which had caused the formerly filled spaces to collapse. Images of the interstitium were captured by electron-microscopy probes.

We recently caught up with Theise to chat about about the discovery. Here’s what he had to say:

Experience Life | What is the interstitium and what does it do?

Neil Theise | The interstitium has been defined historically as the “third space,” after the cardiovascular system and the lymphatics. It has generally been described as merely “the space between cells,” though occasionally the concept that there is a larger interstitial space has been generally referred to, though its anatomic or histologic features have never been described with precision.

It is a space where “extracellular fluid” gathers, i.e., the fluid of the body that is not contained within cells. Some such spaces are obvious: the cardiovascular system containing the fluid of blood, the lymphatics themselves, the space within the skull and spine containing cerebrospinal fluid. These other spaces, however, are estimated to contain only about one quarter of the extracellular fluid. The majority — approximately 20 percent of the fluid volume of the body, comprising approximately 10 liters — is contained within the interstitium.

This interstitial fluid is conceived as being the “pre-lymph” that eventually becomes the fluid in the lymphatic system, and so the space is in direct continuity with the lymphatics and the lymph nodes.

Little else has been known of it until now.

EL | The interstitium was basically hiding in plain sight. How was it discovered?

NT | Doctors Petros Benias and David Carr-Locke, with whom I had a close working relationship, showed me pictures of the wall of the bile duct that they had obtained using a new kind of endoscope. Endoscopes are the snakelike tools that clinicians can use to reach into the body, examining internal organs such as the upper and lower digestive tracts, and to take samples of tissue as biopsies for diagnosis. As a pathologist, I had examined many of the specimens obtained by my two colleagues.

This new scope, however, had a new capacity: after injecting a little fluorescent dye into the vein of the person undergoing endoscopy, the scope could examine living tissue at the microscopic level, similar to what I do with the biopsies at the microscope.

This scope had a fixed focal length, meaning it could only look at one depth: about one-tenth of a millimeter. In most places they and other clinicians using the scope had looked — the esophagus, stomach, small and large intestines — nothing unexpected was revealed. But in the bile duct, a pattern of spaces was revealed that did not match any known anatomy of the bile duct.

So they came to me, as an expert in microscopic examination of tissues specializing in the liver and bile ducts, to see if I could explain what they saw. To my dismay, I could not.

We finally devised an approach observing the bile duct in patients who were about to have cancer operations in which some of their normal bile duct would be removed. Rather than process the sampled bile duct tissue as usual, with dehydration and chemical (formaldehyde) fixation to make slides, we quickly froze the tissue, keeping the resected piece as close to the normal living tissue as possible.

Then we saw the unexpected. The middle layer of the bile duct — long thought to be densely compacted connective tissue, a wall of dense collagen — was actually an open, fluid-filled space supported by a lattice made of thick collagen bundles.

After recognizing this surprise in the bile duct, I quickly realized that every dense connective tissue layer of the body — the linings of all the visceral organs, the dermis (second layer of the skin), all the fascia between and around muscles, all the connective tissue around every blood vessel (arteries and veins of every size) — were like this | open, fluid-filled spaces supported by a collagen-bundle lattice.

EL | Why wasn’t the interstitium identified before now?

NT | Standard processing of tissue for making slides usually involves dehydration. Just taking a bit of tissue from this space allows the fluid in the space to drain and the supporting collagen bundles to collapse like the floors of a collapsing building.

We would often see little “cracks” between collagen bundles in these layers. I was taught, and in turn taught many of my trainees, that these cracks were artifacts of processing: We had pulled the tissue too hard in preparing the slide and separations had formed. But these were not artifacts: These were the remnants of the collapsed spaces. They had been there all the time. But it was only when we could look at living tissue that we could see the real, not the artifact.

EL | Where was lymph thought to have come from previously?

NT | From between cells and the “third space,” whatever that was.

EL | What impact could a better understanding of the interstitium have on medicine?

NT | One can’t understand the mechanical properties of any tissue without understanding the lubricating and shock-absorber potential of the interstitium. These line or surround parts of the body that move: skin and muscles as you move your body, peristalsis as food moves from top to bottom through your GI tract, the expansion and contraction of your lungs with breathing, the squeezing of the bladder during urination, the pulsing of arteries and veins. We’ve never asked, “How do dense connective tissue layers survive such continual stress without tearing or rupturing?” Now we know: They are not dense connective tissue, they are distendable and compressible fluid-filled spaces.

We have known for decades that invasion of cancer into these layers is the moment cancer is at risk for spreading outside the organ, particularly to lymph nodes. Why would invasion into a dense wall of collagen potentiate that? Because that isn’t the anatomy. The space is a fluid-filled highway, often under pressure, that flows directly into the lymphatics and, thus, to the lymph nodes. Tumor metastasis is dependent on this space and its qualities.

Macrophages, the cleanup crew of white blood cells, traffic in this space. When one gets a tattoo, this is the layer in which the pigment deposits and is consumed by these cells. When some of the cells move from here they always wind up in the lymph nodes, like the tumor cells. But unlike the tumor cells, they are performing a normal immune function. Inflammatory cells of all kinds are likely to travel through this space during injury or disease; in direct connection to the lymphatics, they probably play an important role in inflammation.

There is a novel cell type in the organ as well: cells that mix features of the fibroblasts that make collagen (and scar) and endothelial cells that line vessels. But this hybrid combination seems unique to the interstitium. There are several lines of investigation that suggest they may be a long-sought but not-yet-identified source of scar in diseases where fibrosis plays a dominant role (e.g., idiopathic pulmonary fibrosis, scleroderma). These same cells also share features of mesenchymal stem cell, an adult stem cell that can be isolated from nearly all tissues, but whose location in most tissues has remained a mystery.

EL | What qualities makes the interstitium — or any organ, for that matter — an organ?

NT | The definition of “organ” is imprecise, but it usually implies that there is a unity and uniqueness of structure or function. This space has both: unique properties and structures not seen elsewhere and functions that are highly specific and dependent on the unique structures and cell types that form it.

Some people have pushed back, questioning how we can call it “new” if the interstitium has been discussed for more than a century. The reason is that the anatomy, cellular and matrix components, and bodily distribution of the macroscopic interstitium we are describing now have never been described in this detail. Dense connective-tissue layers of the body, re-visioned by this work, are not just “connective tissue” but a macroscopic organ. Detailed discussions of “interstitium” in most of the research literature focus on the microscopic spaces between cells and have not consistently investigated this newly recognized structure, either at the larger scale or in the full distribution throughout the body.

EL | Another “new” organ, the mesentery (a fold of membrane that attaches the stomach, small intestine, spleen, pancreas, and other organs to the posterior wall of the abdomen), was designated just last year. Is there a reason for this recent boom in new organs?

NT | New techniques for examining tissues always lead to new concepts not thought of before. For the mesentery, the tissue was recognized, but it was thought of as “just” fat, inert and uninteresting. New techniques for studying physiology revealed a highly organized functional organ.

In the case of the interstitium, this new ability to look microscopically at living tissue made all the difference.

EL | Can you speculate on other functions that the interstitium might affect?

NT | There are many complementary-medicine techniques that have been proven to have therapeutic efficacy but, in the absence of mechanistic explanations of the sort prized in Western medicine, remain poorly understood or even scoffed at over all. Acupuncture, pulse diagnosis in Tibetan and Chinese medicine practices, myofascial-release therapy, for example, are all techniques that may find some mechanistic explanations in the interstitial structure and properties.

For example, some data suggests that sound waves through tissue are related to the placement of acupoint needles, but the nature of how such sound waves are propagated has been lacking. But the tips of those needles reach into the dermal interstitium. Could the arrangement of the collagen bundles dampen sound waves off the meridian and promote propagation along a meridian channel not previously viewed?

Likewise, the collagen bundles themselves are interesting. Collagen arrays are known not only to conduct electricity but to create electrical current when bent. As already mentioned, interstitial spaces are often, if not always, in movement: Does this generate electrical activity and communication through the network of the collagen lattice? What effects on that conduction occur with pressure or introduction of a moving or charged needle into the space?

These are both reasonable (and perhaps related) physiologies that may help to build a mechanistic understanding of acupuncture.

More questions arise than are answered, but that’s true of all the best, most exciting science!

EL | How does it feel to discover a new organ? A bit like discovering a new planet, perhaps?

NT | This is not my first time making a paradigm-shifting discovery. Eighteen years ago, I was one of the pioneers of adult-stem-cell plasticity that led to President George W. Bush’s 2001 stem-cell address to the nation. It’s quite a humbling experience, actually — not jump-up-and-down exciting in the moment, more like quiet awe.

Most discoveries I’ve made, I can see the implications of in two or three steps. The kind of work I do means a new diagnostic approach, a new therapeutic question raised — but you can see where it’s headed directly and it’s kind of limited, however valuable. These bigger kinds of discoveries are like you’re playing with dominos and you push the first and it hits the second, then the third, then the fourth, and then you look up and realize there are paths of dominos extending in all directions and out past the horizon and you can hear them falling and you realize it’s just so far beyond anything you can imagine in terms of impact. One can’t begin to imagine where it will lead.

is an Experience Life deputy editor.

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