EXTRACELLULAR MATRIX

The extracellular matrix is a network of proteins and other molecules in the space between cells. It helps cells attach to one another and move around. You can think about this like scaffolding for building a house: it provides support and structure for all kinds of activities inside the cell without getting too involved in how those things happen. When there’s damage or injury, it also sends signals to help repair or replace damaged parts of tissue by recruiting stem cells from elsewhere in the body. In this blog post, we will explore how extracellular matrix regulation works to maintain homeostasis from birth to death so you can better understand your body’s natural aging process!

WHAT IS THE EXTRACELLULAR MATRIX?

The extracellular matrix (ECM) is a dynamic structure that provides a structural framework for cellular organization and movement. It is a three-dimensional space, extending between cells that are defined by components produced by the cells themselves as well as cells that they neighbor.

The ECM consists of a dynamic mixture of structural proteins which are typically secreted from the cell into the extracellular environment. The extracellular matrix is made up of many components, including molecules like collagen and elastin, macromolecules like glycoproteins or proteoglycans, proteins like adhesion proteins that allow cells to bind to each other, growth factors that signal new tissue formation, and others.

Collagen is one of the most prominent components of the extracellular matrix. It provides strength and stability to tissues and is primarily responsible for wound healing and tissue repair.

There are many types of glycoproteins, or proteoglycans, which give the matrix its winding appearance, similar to DNA’s iconic double helix. These macromolecules allow cells to recognize and bind to the matrix components.

Several types of adhesive proteins promote cell-to-cell contact, which can be found on either side of a plasma membrane where they’ll spread out from the cell’s surface towards the extracellular matrix. These proteins will crosslink, or bond together with other adhesive proteins to form a mesh that reinforces the adhesive bond between cells.

4 Major Purposes of the Extracellular Matrix:

Containment of cell growth: This refers to how the matrix can “wrap” around cells while still allowing them to grow in size while confined by the surrounding ECM.

Cell signaling and communication: Cell signaling and communication refer to how cells can send signals through the matrix so that growth and development happen in the right place at the right time.

Binding cells together to form tissues or organs:  The adhesion proteins that hold cells together can also link them to the extracellular matrix.

Removal of dead or damaged cells from the body:  Cells are constantly dying and being replaced, so the ECM will send signals to attract stem cells that can migrate towards their location within tissue in order to repair or replace damaged cells.

HOW DOES THE EXTRACELLULAR MATRIX REGULATE CELL BEHAVIOR?

The extracellular matrix is a critical mediator of cell behavior. In fact, cells respond to their environment by changing shape and altering gene expression in order to perform their job properly. 

Cell adhesion: This refers to how cells bind together very tightly with adhesive proteins that can crosslink with other adhesive proteins across the plasma membrane so they strengthen the bond between cells.

In order for cells to join together correctly at the right times and places, they need to be able to sense their environment and respond by sending signals through a network of proteins that bind together in a very specific way. So if a developing embryo is going to form into multiple layers that will eventually become distinct tissues or organs, cells in each layer will need to bind to the ECM and pass signals through it to be able to change shape and function into whatever they’re supposed to become.

3 Types of Cell Adhesion:

Integrin: These proteins anchor cells to the extracellular matrix, primarily binding between adhesive proteins on one side of a plasma membrane and “integrin-binding sites” on the other side of the plasma membrane.

Cell-matrix adhesion: This refers to how cells can bind directly to ECM components, which involves integrins as well as other types of adhesion proteins.

Compartmentalization/Segregation: This refers to how cells can create closed boundaries that will separate different tissues from each other.

In order for cells to be able to create compartments, they need to regulate the way substances enter and exit the local environment. In fact, many types of tissue have a limited list of molecules that can diffuse across their borders in one direction or another – this is called “selective permeability”, and it’s a feature of many cell types.

2 Main Features of Selective Permeability:

1) Pores in the plasma membrane allow solutes to move through them but prevent water from moving freely through those pores, due to the presence of lipid bilayers. This allows cells to selectively control which molecules can enter or exit their local environment.

2) Cells can have a different level of permeability in different directions, so some proteins will move freely across the cell membrane while others cannot – this is called “anisotropy”.

HOW DOES SELECTIVE PERMEABILITY WORK?

Different types of cells can adjust how permeable their plasma membranes are to help create local boundaries and also take in the right molecular nutrients for their job. In regards to the extracellular matrix, the ECM can bind to integrins on the plasma membrane of cells, which helps create a boundary that separates tissues from each other. Integrins are the major cell adhesion proteins, which means they bind cells to the ECM. Cells will be able to pass molecules through the border into neighboring tissues, but if the molecule is too large it won’t fit through the pores of the membranes and therefore cannot go across. All cells have distinct levels of permeability in different directions to help create a very specific environment for each cell type.

EXTRACELLULAR MATRIX & LONGEVITY

Part of what allows cells to remain differentiated is the extracellular matrix. It provides cells with the appropriate molecular signals to maintain their state, and when they move to a different tissue it also helps ensure that they will behave correctly in their new local environment – which is why this system breaks down when there is damage or disease. Abnormalities in the extracellular matrix are linked with age-related diseases. When ECM is broken down, it releases many different molecules that can cause inflammation. Inflammation is an immune response meant to eliminate threats to the body, but chronic inflammation can be very harmful and eventually result in death. When this happens over time the extracellular matrix will degrade and build up in ways that are detrimental to our health. When this happens, it causes “inflamm-aging” which is when inflammation builds up over time due to wear and tear on the body.

As we age, the extracellular matrix continues to degrade in many ways. The aging process involves many deleterious changes in the cells and tissues of an organism, which can affect how it functions. Lifestyle factors may accelerate the degradation of the extracellular matrix. Since ECM is responsible for cellular differentiation, preventing this degradation could lead to greater longevity because it would allow cells to maintain their state and continue functioning properly.  

Disclaimer: The content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Additionally, the information provided in this blog, including but not limited to, text, graphics, images, and other material contained on this website, or in any linked materials, including but not limited to, text, graphics, images are not intended and should not be construed as medical advice and are for informational purposes only and should not be construed as medical advice. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Before taking any medications, over-the-counter drugs, supplements or herbs, consult a physician for a thorough evaluation. Always seek the advice of your physician or other qualified health care provider with any questions you may have regarding a medical condition or treatment and before undertaking a new health care regimen, and never disregard professional medical advice or delay in seeking it because of something you have read on this or any website.

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CELL DANGER RESPONSE: What it is and why its important

The body’s immune system is a complicated, elegant machine that protects us from the outside world. It does this by recognizing invaders through amazing sensing mechanisms and responding to them with incredible precision. In the case of cell danger response (CDR), our cells do their best to protect themselves as they are being attacked by viruses or bacteria. Yet CDR can be dangerous if it overreacts and causes inflammation – which can lead to chronic diseases such as diabetes or even cancer. In this week’s blog post we will not only explain what CDR is but also how we minimize its risks so we may live a healthy life.

WHAT IS THE CELL DANGER RESPONSE?

The cell danger response (CDR) is the evolutionarily conserved metabolic response that protects cells and hosts from harm. 

How it works is by the cell senses that it is being attacked, then using specialized proteins to monitor our metabolism. When CDR is activated, the body will use available energy sources and switch its focus to self-defense rather than growth and reproduction. CDR is a mechanism that allows cells to sense ‘danger’ that may be caused by viruses or bacteria. This danger can also come in the form of molecules such as DNA, RNA, and proteins – all of which are components found inside our cells.  When these substances get leaked into the extracellular environment, CDR kicks into gear.

The activated CDR will then enter into a cascade – this is where it gets its name, the danger response cascade (DRC). The danger response cascade can be broken up into five steps that occur in succession: 

1. Detection: Detection of PAMPs (e.g., pathogen-associated molecular patterns like lipopolysaccharides) or damage-associated molecular patterns (DAMPs). PAMPs are substances that can be recognized by specialized receptors, such as Toll-like receptor (TLR), NOD-like receptor (NLR), and RIG-I like helicases (RLH). DAMPs refer to the cellular debris or damage that results from being attacked. 

2. Activation of MAPKs, IKKɛ, TBK1, PKA, and PKR. Next these activated enzymes activate transcription factors (which refers to a biochemical process by which a particular gene’s instructions are copied into RNA) that then activate or suppress inflammation-promoting genes while suppressing other essential genes involved in repair pathways. When we discuss activated enzymes, this refers to enzymes that have been phosphorylated, which means a phosphate group has been added to the enzyme.  

3. Activation of transcription factors such as NF-kB, FOXO3a, and HIF1α. These transcription factors then go on to stimulate or suppress the transcription of genes that regulate inflammation and also cell survival. 

4. Activation of MDA5 & RIG-I: MDA5 and RIG-I are critical to the CDR response because they activate an antiviral pathway known as type I interferon production. Type I interferon production is a pathway that allows our body’s immune system to help fight infections. 

5. Secretion of inflammatory cytokines to induce downstream immune cells to take action against the infection. Inflammatory cytokines are a group of signaling proteins that trigger inflammation at sites of infection. The cells which release these cytokines are called antigen-presenting cells (APCs) and include monocytes, macrophages, dendritic cells, and B lymphocytes. This cascade is what allows CDR to induce inflammation – yet it can have negative consequences if activated over and over again.

In addition, CDR can also occur in response to non-infectious stresses such as heat, UV irradiation, and oxidative stress. These stresses have been shown to activate IKKɛ (which is one of the last components in the cascade) and cause it to activate NF-κB (Nuclear factor-kappa B). When activated, this protein moves into the nucleus where it works with other transcription factors to promote the expression of genes that trigger inflammation. It is important to note that these events happen within minutes of your body detecting CDR triggers. 

WHAT IS THE DANGER RESPONSE CAUSED IN THE BODY?

Inflammation is a vital part of the CDR cascade. It’s what helps cells fight off disease, but there are consequences if it goes on for too long or isn’t properly regulated.  Left unchecked, inflammation can lead to several chronic conditions. 

 Inflammation has been linked to cardiovascular disease, arthritis, atherosclerosis, type 2 diabetes, Alzheimer’s disease, and even depression. One of the most well-known links between inflammation and chronic illness comes from the research of Dr. Robert Ader. In 1974 he conducted a study in which two groups were given an antitoxin to protect against poison. 

 Group A only received the treatment, while group B also had their spleens removed beforehand to prevent their immune systems from mounting an inflammatory response. After receiving the antitoxin both groups were then injected with the poison. However, unbeknownst to them this second injection was not actually poisonous but just saline solution therefore they should not have gotten sick. 

To the surprise of the researchers, group B got just as sick as group A even though they did not have an immune system. Basically, because their bodies had already mounted an inflammatory response when injected with the saline solution it was interpreted by their brains to be a poison so they could become ill. This example is just one of many that illustrate how chronic inflammation can lead to the development of disease.

HOW CAN WE AVOID THE DANGER RESPONSE?

The answer to this question is multifactorial. First, it’s important to avoid or control infections with your immune system because that is what triggers the response in the first place.  

Second, it’s also best to take care of your body. This means eating a healthy diet, exercising regularly, practicing stress management, and more. 

Third, optimizing your immune system is important.  The better it functions the less likely you are to succumb to disease and the more effective it will be at fighting off infections.

Fourth, protect your cells from damage and stress by limiting exposure to toxins and sources of oxidative stress such as UV radiation and environmental pollutants. This includes using antioxidants that can directly neutralize free radicals before they do damage: vitamin C, vitamin E, manganese, selenium, copper, zinc, and more.

Finally, genetic variation also determines how many times your immune system can mount a CDR response before producing dysfunctional cells. This means that although the danger responses in everyone are the same there is a big difference in their potential scope because of individual genetics. Different SNPs have also been linked to an impaired danger response.

Although the danger response is an important part of fighting infections, it can also be responsible for chronic inflammation which has been linked to many health problems. Fortunately, there are things you can do to prevent this from happening. By implementing lifestyle changes you can help your body fight off disease while simultaneously protecting your cells from damage. 

How can the Institute for Human Optimization help you? At IfHO, we utilize a personalized, precision-based approach to medicine. Precision Medicine acknowledges individual differences in genes.  By having a better understanding of the individual’s genes and making therapeutic decisions based on their genetics, we can work together to drive CDR in a desirable direction.   

Disclaimer: The content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Additionally, the information provided in this blog, including but not limited to, text, graphics, images, and other material contained on this website, or in any linked materials, including but not limited to, text, graphics, images are not intended and should not be construed as medical advice and are for informational purposes only and should not be construed as medical advice. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Before taking any medications, over-the-counter drugs, supplements or herbs, consult a physician for a thorough evaluation. Always seek the advice of your physician or other qualified health care provider with any questions you may have regarding a medical condition or treatment and before undertaking a new health care regimen, and never disregard professional medical advice or delay in seeking it because of something you have read on this or any website.

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