Nature’s Scaffolding: the Extracellular Matrix
Gage Haden
Illustrations by Hanqi Wu
Imagine walking through New York City, neck craning as you stare, agape, at the giant skyscrapers and buildings at every turn. Now, focus your attention on the buildings still under construction and the protected walkways between buildings. The city itself is supported and reinforced by lattices of metal piping, a steel exoskeleton of scaffolding, often overlooked, yet essential to the construction and safety of citizens. The scale of this scaffolding is enormous, but the principle is universal. Scaffolding supports everything from the largest skyscrapers to the minuscule cells of our bodies. Hidden between the 37 trillion individual cells of our bodies is another essential structure for life: the extracellular matrix (ECM). The ECM is a complex, variable biological scaffolding that surrounds each of our cells, giving them structure and keeping reserves of important messenger molecules [1, 2]. In the central nervous system (CNS), made up of our brain and spinal cord, the ECM plays an important role in fortifying neurons. The central nervous system is our command center, receiving, interpreting, and sending information to direct the actions of the rest of our bodies. This information is passed as electrical signals from one neuron to the next in pathways that generate specific commands. Thousands of these pathways exist in the human brain, all connecting and branching to create neuronal networks responsible for more coordinated information processing and command issuing. Surrounding these networks is the ECM, hard at work stabilizing the neural connections and stabilizing the structure of the CNS.
The Building Blocks of the ECM
The ECM in the central nervous system works to maintain healthy brain function through a variety of mechanisms, including establishing structure [3]. This neuronal scaffolding consists mostly of proteins and carbohydrates bound together, designed to support brain function by allowing an increase in the rigidity of the structure [4]. The ECM makes up roughly 10-20% of the total volume of the brain and is composed of three distinguishable components: the basement membrane, perineuronal nets (PNNs), and the interstitial matrix [5]. The basement membrane is aptly named; similar to a basement separating a building from its foundation, the basement membrane separates the main parts of the brain from their surroundings [6]. Perineuronal nets, like bearing walls in a building, surround the cell bodies of neurons and provide structural solidity to neuronal networks [3]. PNNs are imperative for regulating the adaptability of our brains as well as developmental growth. Finally, the interstitial matrix, made up of all other ECM molecules dispersed throughout the CNS, provides storage for important molecules in the CNS [1].
Modeling the Brain: The ECM in Development
As the nervous system matures, a person’s interaction with their environment alters the formation and reinforcement of frequently used neural networks [7]. The networks in our brains are specific to the ways we live; for example, people who are born deaf have different neural networks for language than those who are born with hearing [8]. People born without hearing require less auditory interpretation and consequently, the networks specific to this function will not develop the same as in a person born with their hearing [8]. As the brain develops, certain networks are built up and others removed as specific environmental conditions narrow down what functions are more important for the survival of an individual [9]. Imagine this process like the remodeling of a house: contractors take out unwanted walls while fixing up the walls still important to the house’s structure. The ability of the nervous system to remodel its networks in this way is reliant on the principle of plasticity — the malleability of the brain and its ability to rewire neural pathways [9].
The brain’s capacity for this rewiring changes throughout development; plasticity is not constant in the CNS. During development, there are specific time periods in which plasticity is dramatically increased, known as critical periods [7]. Critical periods are important for the development and refinement of complex functional networks; the brain’s increased flexibility allows for more rapid growth and development [9]. Following these critical periods, plasticity is then decreased by building up structural components, such as perineural nets, which bind the intact networks that have been formed and refined during the critical period [10, 11]. Neural plasticity changes throughout development and is driven by the formation and movement of various ECM components [7]. Plasticity and structure are opposing forces in the brain, and without a delicate balance between them, the nervous system is left vulnerable.
Disrupting the Balance: ECM Abnormalities in Illness
Neurological disorders often affect the ECM in the brain. Abnormalities in the human ECM are associated with schizophrenia, a chronic psychotic disorder, and Alzheimer’s disease, an aggressive form of dementia [12, 13]. Soon after these associations were found, scientists corroborated the results by experimentally disrupting the ECM in mice, leading to significant alterations in schizophrenia-related neural networks [14]. The ECM disruptions most commonly found in individuals with schizophrenia are the loss of functional perineural nets and altered expression of ECM molecules within neuron support cells [14]. These support cells, called glial cells, protect and reinforce neurons as well as provide them with essential oxygen and nutrients [15, 16]. Without the ECM, glial cells cannot properly support the function of neurons [14]. An increase in neural plasticity, caused by lower levels of ECM, is correlated with schizophrenia; the decreased structure results in the breakdown of essential neural networks [12, 13]. Plasticity benefits the growth and learning of the brain during development, but once the brain is mature, it leaves functional neural networks without support from the ECM. Therefore, these networks are vulnerable to degradation.
Alzheimer’s disease, a degenerative and progressive neurological disorder associated with the buildup of plaques in the brain, is associated with a different disruption in the ECM [12]. The plaques clog up the brain, similar to how a blood clot obstructs a blood vessel, and studies linking Alzheimer’s to the ECM found structural components of the neural ECM within the plaque build-ups [17]. More research is needed to reveal the entirety of the role these molecules have in the cause and effects of the disorder, but it is clear that Alzheimer’s is using ECM building blocks in ways they were not evolutionarily intended. The disruption of the ECM is involved in a wide variety of neurological disorders, each with a different mechanism of action [12, 14]. Certain disorders lower expression of ECM-related molecules, while others increase expression, indicating that the ECM must be kept in a delicate balance [13, 17].
Adding Insult to Injury: The ECM in Brain Injury
When an injury occurs in the central nervous system, cells that increase the production of ECM components are activated, thus increasing the structural rigidity surrounding the area of injury [18, 19]. Immediately prior to reinforcement of the injured CNS, a new critical period opens, when plasticity has not yet decreased, and recovery potential is at its highest [20, 12]. This is why a speedy response to brain injury is important for good long-term outcomes: it is crucial to take action before plasticity is obstructed by the ECM [20]. Similar to how the expression of ECM components is related to mental disorders, the fluctuating ECM-propelled balance of rigidity and plasticity poses benefits and vulnerabilities following traumatic injury [18].
Similar to cuts and wounds forming scars as they heal, scar tissue also forms around injured areas of the brain and spinal cord [22]. This scar tissue is made of neuron-supporting glial cells, neuroimmune cells, and ECM components, blocking the spontaneous regeneration of neurons and their networks. While at other times, the increase of ECM components is beneficial, in this case, it hinders the recovery of damaged neural networks [22]. Plasticity is a powerful tool of the nervous system, both in development and recovery. Without the proper regulation of ECM components, however, plasticity is either over-heightened or lowered, causing issues in health and recovery potential.
Matrix Medicine: Clinical Applications of the ECM
The extracellular matrix is an essential component of the CNS and works to keep our body’s command centers in a healthy equilibrium. The ECM balances the brain’s inherent plasticity with an equally important need for structure. Based on these characteristics, the ECM has emerged as a potential clinical target for the treatment of numerous neurological issues [23]. There are two basic approaches to clinical treatments with the ECM: increasing structure by stimulating the formation of ECM components, or implanting synthetic copies and conversely increasing plasticity by dissolving the present ECM [23]. These opposing approaches, increasing either structure or plasticity, are applied in many different ways.
Attempting to increase the structure and stability of neural pathways is effective in improving nerve transplantation techniques [24, 25]. When implanting cells intended for regeneration, or intact nerves as a transplant, synthetic ECM substitutes increase the benefits and success rate [24, 25, 26]. This technique works similarly to vines of ivy climbing a trellis. Without the trellis, the vines grow jumbled on the ground and are less healthy. With the trellis or our synthetic ECM, the nerves or stem cells have a path and structure to grow on, resulting in healthier grafts growing in precise, specified directions. These same regenerative benefits can be achieved by stimulating cells that naturally create and release ECM components or by implanting extracted brain-derived ECM components [27, 28, 29].
Other treatments seem to contradict the idea of the structural “trellis” and instead focus on dissolving the ECM to allow for enhanced mobility and growth of neural cells [30, 31]. Depending on the abundance and location of ECM components in the CNS, they can either act as a trellis or an impenetrable wall. PNNs, especially, seem to aggregate at traumatic brain injury or neurodegeneration sites, providing structure for the scar tissue that forms in the space and leaving no room for our “vines'' to regrow [32, 33]. Enzymes can dissolve these ECM components, allowing damaged neurons to heal their appendages and restore disrupted neural networks [30, 31].
Conclusion
Therapeutic approaches to the ECM seem to be two sides of the same coin, one increases structure and decreases plasticity, and the other does the opposite, showing the great complexity of ECM interactions in the CNS. Both approaches have been shown to be beneficial in medicine when used properly and at the right time point following damage to the CNS. Targeting the neural ECM has great potential as a clinical approach but is similar to balancing on a double-edged sword; leaning too far in either direction is dangerous. Much more research on neural ECM interactions in disease and injury is needed to improve the potential clinical solutions. Because of this, we are only beginning this grand scientific journey.
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