Bringing nerve regeneration from tank to bedside: an interview with Dr Sandra Rieger

Written by Freya Leask

In this interview, Sandra Rieger, PhD, Assistant Professor at the MDI Biological Laboratory (ME, USA), discusses how her lab is utilizing zebrafish as a model to study wound healing mechanisms and nerve regeneration in patients with peripheral neuropathy.

The MDI Biological Laboratory (ME, USA) is a growing independent biomedical research institution. It aims to improve human health and well-being through basic research and development ventures, as well as providing world-class science education.

In this interview, Sandra Rieger, PhD, Assistant Professor at the MDI Biological Laboratory, discusses how her lab is utilizing zebrafish as a model to study wound healing mechanisms and nerve regeneration in patients with peripheral neuropathy

Sandra Rieger, PhD
Sandra Rieger, PhD, is an assistant professor at the MDI Biological Laboratory. She holds a doctorate in developmental neurobiology from the Institute of Developmental Genetics at the Helmholtz Center (Munich, Germany) and conducted postdoctoral research at the University of California, Los Angeles (CA, USA), in neural regeneration.

She is studying sensory nerve regeneration in peripheral neuropathy — a potentially disabling condition causing numbness, tingling, temperature sensitivity and pain in the hands and feet. Peripheral neuropathy can be caused by factors including chemotherapy, diabetes, alcohol, infectious disease and hereditary disease. Rieger has established a zebrafish model to study the signaling mechanisms leading to peripheral neuropathy caused by paclitaxel, a chemotherapeutic agent. She has identified two potential therapies that target the enzyme matrix—metalloproteinase 13 (MMP-13) in the epidermis and has discovered that the inhibition of this enzyme promotes nerve repair and prevents nerve degeneration in zebrafish. She is studying both compounds for their effects in mammals.

How did you come to work in the MDI Biological Laboratory?

When I was a post doc I looked at potential independent investigator positions and I was fascinated by the MDI Biological Laboratory’s institutional approach, which focused on regeneration biology using animals that have a naturally high regenerative capacity. Investigators here, including myself, use zebrafish and also salamanders to study natural regeneration processes.

Personally, I am interested in using zebrafish, especially the larvae and developing zebrafish, because they have a very high regenerative potential. They are also optically clear, so we can visualize regenerative processes in the living animal. Primarily, I’m utilizing time-lapse imaging to look at sensory nerve regeneration and wound repair processes. I like to watch these animals in real time; it can be a very powerful tool.

What is it that interests you in wound healing and regenerative medicine?

I am interested in trying to identify medications or treatments for human diseases, but I’m also interested in the basic mechanisms of wound healing and regeneration. When I was a post doc in the lab of Alvaro Sagasti (University of California, Los Angeles), I started to look at the mechanisms by which wounds heal and I became very interested in the role of sensory nerve endings in this process.

Very little is known in the field about how sensory nerve endings interact with wounds, particularly skin wounds. Since zebrafish regenerate their fins really well, we can amputate their fins and watch regeneration in live animals. I found that not only the fin but also the nerve endings regenerate well. I discovered that nerve regeneration is stimulated by the small reactive oxygen species, hydrogen peroxide, which is secreted by wound epidermis. If we can genetically eliminate the enzyme that produces hydrogen peroxide, nerve endings don’t regenerate anymore. We know from other studies that nerves in the skin are really critical for wound repair processes; if you don’t have nerves in the skin the wound doesn’t heal properly. For instance, diabetic patients with peripheral neuropathy, a condition of nerve degeneration in the skin, often develop wound healing defects due to the lack of sensory nerve endings. This is because nerve endings secrete certain molecules or trophic factors that promote the healing process. I am very interested in those mechanisms — how does the wound and specifically the skin cells in the wound interact with nerve endings under conditions of peripheral neuropathy?

Why are you using zebrafish as a model for your studies as opposed to other model organisms, such as the mouse?

The larvae of the developing zebrafish are optically clear so we can utilize them for time-lapse imaging, which is very powerful. You also get hundreds of eggs from a single mating, so we can utilize lots of animals at the same time, giving higher statistical power. Another feature is that they develop very rapidly. I can start doing the analysis within 2 days of mating the parents and collecting the eggs because the larvae have already developed to a point where nerves have innervated the skin and are fully functional.

Furthermore, these fish have a very high regenerative capacity compared with mammals, so they are better for studying regenerative processes. Lastly, what I think is also very powerful is that approximately 80% of the genes known to cause diseases in humans are also present in zebrafish, so we can use the model to really learn about these diseases and apply this knowledge to humans.

What are the challenges you have come across in your research?

I think one of the big challenges is that zebrafish research is still not as accepted as research in mice, meaning that it is more difficult to get funding for zebrafish research. The zebrafish community will have to provide better demonstrations that zebrafish are a good model to study human diseases. In fact, the National Institutes of Health (MD, USA) recently offered some workshops specifically geared towards translational research from zebrafish to human treatment, called Tank to Bedside. While the National Institutes of Health have recognized that zebrafish are good models, there are still challenges in terms of funding.

Another challenge is that the MDI Biological Laboratory is not directly affiliated with a clinic so it can be hard for us. If we have identified mechanisms that we would like to translate into the clinic, we have to find collaborators in different locations to do so.

What clinical applications could your zebrafish research have?

I am collaborating with the Mayo Clinic (MN, USA) to find a treatment for neuropathy. I’m interested in identifying small molecules that can promote sensory nerve regeneration and wound healing in this condition.

Neuropathy is the collective name for conditions where nerve endings degenerate and I am particularly interested in the degeneration of sensory nerves. In particular, my lab is investigating mechanisms of neuropathy caused by chemotherapy agents, including paclitaxel. This chemotherapeutic agent is mostly utilized for cancers such as breast, ovarian and lung cancer. It causes neuropathy as a side effect in 60—70% patients, with symptoms such as numbness, tingling, pain and temperature sensitivity. Once neuropathy occurs, the condition can be very severe and some patients may have to terminate their chemotherapy prematurely, which deprives the patients of the full benefits of chemotherapy and jeopardizes their life. Survivors on the other hand may suffer continuously from the disease and may not be able to lift a drinking glass or play a musical instrument. At this point, no treatments are available for neuropathy besides alleviating pain.

We have started to utilize zebrafish to model this condition and we have identified that the skin seems to play a role in nerve degeneration. We found that treatment of the fish with paclitaxel causes the skin to have reduced adhesion, the glue between cells, due to an increased activity of matrix-metalloproteinase 13 (MMP-13), a matrix degrading enzyme that paclitaxel stimulates specifically in the skin. We found that there is upregulation, or increased activity, of MMP-13 that seems to degrade the matrix and thereby damage the skin, also affecting sensory nerve endings, leading to nerve degeneration.

In fish, we can block MMP-13 activity with compounds we have identified that prevent sensory nerve endings from degenerating, and that can also partially restore their regeneration. I’m working with Nathan Staff at the Mayo Clinic, where we want to look at human patient samples to see if MMP-13 also plays a role in the skin of paclitaxel-treated patients. If this is successful, we can hopefully begin with clinical studies to see if we can use MMP-13 inhibitors to treat patients.

How important is patient interaction in your work investigating therapeutic approaches for peripheral neuropathy?

For me it’s very important. However, because I am not a medical doctor, I cannot directly see patients — I rely on clinicians to help me with these studies. Right now, the first goal for Nathan and me is to look at human patient samples. We will also perform simultaneous studies in mice and rats to see if we can recapitulate the findings from zebrafish in these models. Once we have collected evidence in mammalian species and we have tested the MMP-13 inhibitors for their efficacy, we can begin developing clinical applications — for example, we could try skin emulsions that contain the inhibitors on human chemotherapy patients. The lotion could be applied to th e patient’s hands and feet where neuropathy typically starts, and this could prevent neuropathy during chemotherapeutic treatment.

What are the next steps in your research?

Right now, we’re starting to look at mice and also rat models. I’ve applied for funding to look at rat models because they seem to mimic neuropathy better than mice. This will be a very important step — we will administer paclitaxel to rats with the inhibitors and do skin analyses to see if MMP-13 is regulated or active in the skin. That’s my most important goal within the next few months.

Where do you see the field of regenerative medicine for wound and nerve regeneration heading in the next 10 years?

I hope that more research is being performed on the interactions between skin and sensory nerve endings and that scientists will look more into the mechanisms underlying the degeneration of nerves by focusing on the skin. This may reveal new treatments for neuropathy.

I hope that in the future more small molecules or chemical compounds that promote regeneration will be identified. While there is a big push for stem cells, this field has its own challenges as it is not well understood yet how they behave inside the body. I think that induced pluripotent stem cells are more promising; however, these also do have the potential to cause cancer due to uncontrolled cell division. Therefore, I believe a better approach to promote regeneration at this point is to use of small molecules. Small molecules will definitely be gaining more interest for their ability to promote regeneration.

Are there any conferences you are looking forward to visiting in 2017, or other research that you will be following?

I will likely be participating in the Gordon Research Conference on Tissue Repair and Regeneration, which takes place every other year in New Hampshire, USA, and I also plan attending the Society for Neuroscience’s 47th annual meeting, Neuroscience 2017, in November.


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