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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When Your Advisor Changes Universities….

A personal anecdote of my decision to move to a new university with my PhD advisor

Things have been pretty hectic here in the Wollman lab for the past few months, and especially the past couple of weeks, as we pack up our personal lives and lab benches and head north to the other side of Orange County (as my advisor, Roy, likes to say). When Roy first announced to us in May that our lab was moving from UC San Diego to UC Los Angeles in August (only 3 months away) I experienced emotions ranging from excitement to fear to denial. I began to scour the internet searching for advice on whether to remain physically at UCSD or follow Roy to UCLA, but all I found were personal anecdotes of other graduate students in similar situations. What I realized was that the decision to stay or move is highly personal and depends on a number of factors. So, here I add my personal anecdote to the conglomeration of internet information. Hopefully my story will be helpful to fellow graduate students facing similar situations.

So you’ve done it. You’ve been admitted to a PhD program, joined a research group, and are chugging along in the research process when your PhD advisor announces that they are moving to a different university. Ugh. It’s not unusual for professors to change universities throughout their career. However, the mixed student/employee status of a graduate student can make the decision to follow your professor to a new university sticky.

Although many graduate students have a tense or otherwise negative relationship with their PhD advisor, my relationship with Roy has been very positive. He has been very supportive throughout my time in his lab of my goals and outside-of-lab endeavors. I can openly discuss my career plans with him without fear of backlash for hoping to leave academia following graduate school. He is patient with me as I learn new techniques and thinking methods. At the time of his announcement I was at the end of my 4th year of grad school. Two weeks prior we had discussed me graduating at the end of my 5th year. When the announcement came my first thought was “I’ll just graduate faster and not have to leave!”. Being this far along in my PhD meant that switching labs would be impossible, meaning if I want to graduate I need to stay with Roy. I didn’t want to leave behind my relationships with friends and colleagues that I had built for the last 4 years, not to mention my beautiful condo just minutes from campus and the beach. LA has more traffic, LA is more expensive (a big deal on graduate student stipend!), LA has too many people etc. I was upset. I wasn’t ready to leave San Diego. Up until this point I had been the decision-maker when it came to moving: I chose to attend BYU for my undergraduate degree and I chose to attend UCSD for graduate school. Furthermore, despite being accepted to both UCLA and UCSD for graduate school, a variety of reasons led me to choose UCSD. Being forced to live in Los Angeles did not make me happy.

That afternoon I spoke with Roy about graduating sooner. As usual, he was understanding and supportive. We outlined a plan where I could defend my thesis in December and work remotely from September to December after the lab had moved. Since UCLA is only a 2 ½ hour drive from San Diego (without traffic, that is), I could still come up once a week to check-in with Roy and the rest of the lab. The plan was to complete a few key experiments before the lab moved and spend my remote time analyzing data and writing papers and my thesis. Leaving that meeting I felt good about this plan. I already had a first author paper in a notable journal in addition to a first author review paper. I moved my anticipated graduation date up by 6 months and would still be able to squeeze one more paper out of my PhD. Sure, the following few months would be crazy as heck, but that’s grad school right? Most importantly, I wouldn’t have to leave San Diego. And that made me happy.

But, there was a problem. What about after graduate school??

At the beginning of my graduate school career I decided to try and follow the advice some older graduate students had given me: Work your butt off until you advance to candidacy. Then, during your last couple of years, reap the rewards of your hard work and let your research do its thing. Use your spare time to pursue other interests that will build your resume, figure out what you want to do after graduate school, look for jobs, etc. I liked this plan and did my best to follow it. My 5th (and final *crosses fingers*) year of grad school was meant for figuring out what I ACTUALLY want to do with my life and finding a career. Speeding up my graduation timeline would mean giving up the luxury of taking time to find a job, pursuing other interests, and spending time traveling over the summer with my sister (I’ve been in school a long time dangit! I want to take some time off J ). Furthermore, the results for my second paper were turning out to be less exciting than originally anticipated. It would be nice to spend some extra time to finish my PhD project on a high note.

And so, I decided to move with Roy to UCLA. After all, it would only be for a year. I have the opportunity to meet new scientists and expand my network. UCLA is only 2 ½ hours from San Diego. The beach is still close and the weather is warm.  And who knows what new opportunities I will find here?!

Officially I am still a UCSD student. Since I have already advanced to candidacy I am not able to transfer to another school. Instead I am considered a “University of California Intercampus Exchange Student”. Basically this means I still have the perks of being a UCLA student, but my tuition is paid to UCSD. Our lab space is completely new and beautiful. My apartment is close to campus. My dogs and I are starting to settle in. So far I’m happy with my decision to follow Roy, even though I miss the familiarity of San Diego. We’ll see what new adventures are ahead!

lajollaoverlook_2016sept07

One of my favorite spots in La Jolla. Only a 10 minute walk from my lab, I would come here when I needed a minute to clear my mind or take a quick break. Of course, I’m in my usual lab uniform of leggings, T-shirt, and a bun on top of my head. I make no claims to be a fashion blogger.