When cells don’t need chemical signals to find a wound after injury

Evolution over millions of years has given us the ability to function in our environment with little conscious thought—our heart pumps blood throughout our body, our digestive system pulls nutrients out of food, and when we get a cut, our body magically heals itself. But what if these things didn’t work? What if we had to tell our heart to contract like we tell our biceps when lifting a heavy box? What if digesting food required conscious thought or wounds didn’t heal? We probably wouldn’t survive very long. Luckily, our “built-in” systems keep us alive and thriving.

One of these built-in systems is wound healing. After getting a cut we might worry about how much it hurts or how long it will last, but we don’t have to consciously focus on healing. In order to function automatically, the cells that work to heal the wound need a way to know (1) that the wound occurred, (2) where the wound is, and (3) the size of the wound. And they need to know quickly. Cells gather this information using sensors that look for specific damage signals called DAMPs (damage associated molecular patterns). DAMPs form chemical gradients that alert surrounding cells that damage has occurred and the location and severity of the wound. (You can read more about DAMPs in my previous post HERE.) But although it has been well established that chemical gradients created by DAMPS are used to alert cells of an injury, scientists in the Philip Niethammer* group asked whether a mechanical sensor that indicates tissue damage would also be possible.

chatty-cells

After an injury, cells need to communicate with each other in order to find and heal the wound.

Unlike chemical sensors, mechanical sensors rely on physical sensations such as motion, temperature, and pressure. One potential biological mechanical sensor is cellular swelling.¥ Cellular swelling can result from tissue stress such as wounding and has been associated with recruiting leukocytes (white blood cells that are essential to protect the body from infection, especially at the site of a wound) to the injury site. The current theory to explain how cellular swelling recruits leukocytes involves the swollen cells rupturing to release DAMPs into the extracellular space (like a water balloon that gets too full and breaks). However, recent studies have demonstrated that cellular swelling can still initiate a wound healing response without cell rupture. These studies bring to light the potential role of mechanical sensors such as cell swelling in wound healing.

The first thing that the Niethammer lab found was that cellular swelling increased calcium (Ca2+) levels in cells surrounding the wound. The increase in Ca2+ caused cPLA2, a type of lipid found commonly in wound response, to move from the nucleoplasm (part of the inside of the nucleus) to the inner nuclear membrane (part of the outer ring, or “skin”, of the nucleus). Using this knowledge, the Niethammer group hypothesized that cellular swelling was sufficient to cause cPLA2 movement within the nucleus.

cellswellingfig

Cellular swelling causes cPLA2 movement from the inner nuclear membrane to the outer nuclear membrane. This process attracts leukocytes to the wound.

To test this hypothesis, the Niethammer group developed a novel method to make synthetic nuclei. Using giant vesicles made from dried lipids, they were able to mimic the “onion-like” inner and outer layers of the nucleus. After adding cPLA2 to the giant vesicles in the presence of Ca2+, they changed the environment of the vesicles to induce swelling. As they hypothesized, when the vesicles began to swell, cPLA2 moved to the outer layer of the vesicle. This means that cPLA2 movement only requires cell swelling and calcium! By working with only the bare minimum, they were able to strongly support their claim that mechanical sensing is possible in wound response which recruits leukocytes to the wound.

These experiments from the Niethammer lab are significant for a few reasons:

  • They have strong evidence to support a mechanism for wound sensing that differs from the current theory for how leukocytes are recruited to a wound. Mechanical sensing for wound response provides an alternative mechanism that may explain anomalies in cellular signaling. Furthermore, different areas of the body may require different sensing mechanisms. When thinking of wounds, you probably first think of wounds that happen on the outer layer of your skin, or your skin epithelial cells. However, there are epithelial cells throughout your body lining your organs and blood vessels to separate and protect them. Cellular swelling as a sensor is applicable to wounds such as those that occur in the digestive tract where the cells are in a hypotonic environment.¥
  • They developed a novel method to mimic nuclear layers that can be used to test how different extracellular environments can affect a cell. The giant vesicles are especially interesting because they reduce some of the complications that come from working with entire cells or organisms. Although it is important to take this complexity into account, a simplified approach allows researchers to isolate specific factors.
  • They show how simple biology can be. One of the beautiful things about biology is that, although constantly evolving to survive in ever-changing environments, it often takes the path of least resistance. That is, sometimes the simplest answer is the correct answer. Although other tissues may require more complicated sensing, biology takes advantage of instances when simple mechanical sensing is sufficient to relay an appropriate response.

*Enyedi, B.; Jelcic, M.; Neithammer, P. The Cell Nucleus Serves as a Mechanotransducer of Tissue Damage-Induced Inflammation. Cell. 165, 1160-1170, (2016).

¥ Cells swell when the inside of a cell is exposed to a hypotonic environment, or environment that has more water than the inside of the cell. Biology needs balance, and in order to balance out the amount of water inside and outside of the cell, water begins to enter the cell—therefore causing swelling.

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