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Amy Wagers' research on tissue regeneration and aging using stem cells caught our attention. Curious to know more, BioTechniques contacted her to find out about the ambition, character, and motivations that led to her success.
Delivering on a Promise
What led you to study stem cells?
When I was an undergraduate at North-western University, I was walking through the student union and encountered someone recruiting people to join the bone marrow transplant registry. I registered and donated some blood. During my third or fourth year in graduate school, my mom called to say that the registry had contacted her; I had matched with someone who needed a transplant. During the screening and typing tests to get ready for the donation, I read a lot about stem cells and bone marrow transplants. In the end, the patient decided not to go forward with the transplant and I decided to look into stem cell biology for my postdoc.
What are the current research goals of your lab?
We are researching the mechanisms that limit the regenerative potential of tissues, particularly in the normal physiological context of advancing age. As you get older, your body's ability to heal itself declines, so we are interested in why that is and whether it is necessary.
In a number of different tissues, resident stem and progenitor cells possess high regenerative activity that declines with age. We have found that we can actually reinvigorate that regenerative activity by exposing old stem and progenitor cells to a young circulatory system using the parabiotic technique, a surgical method for joining the vasculature of two mice. Right now, we are trying to understand at a molecular level what pathways regulate the resident stem cells' regenerative activity.
Have you been surprised by any results obtained during your tissue regeneration studies?
The dramatic regenerative activity seen in the parabiotic experiments was definitely surprising to me. There were some studies in the literature where investigators transplanted minced muscle cells from young animals into old or from old animals into young and showed that the regenerative potential of transferred cells correlated with the host environment; when young cells were placed in an old animal, they regenerated like they were old.
It's not just one tissue that ages, but all of them and we wondered what could be synchronizing that. The blood system seemed like a reasonable place to look. So with Tom Rando and Irina Conboy at Stanford, we set up a parabiosis experiment to bathe the tissues of an old animal in circulating factors found in young animals and then looked at muscle regeneration following injury.
The most enjoyable part of research is when you get a clear result and realize that this particular moment is the first time anyone has known this information. My postdoc, Massimiliano Cerletti, was analyzing the first transplants of muscle stem cells in mice when he found a huge area of muscle engraftment, indicating that the cells were really potent in regenerating muscle. He came running down the hall yelling, “Amy, Amy, Amy, Amy!” We were both jumping up and down because it was so exciting.
That experiment was interesting, but I was really shocked by how effectively it worked. And I continue to be surprised by how universal this dramatic ability to heal has been in the many different tissues we have looked at.
What is the potential for this research?
If we define appropriate targets, we hope to eventually develop drugs for restoring or maintaining healthy tissue function later in life. It's not about extending life, but keeping tissues healthy as they age.
What has been your most significant contribution to your field so far?
When I began my position as a postdoctoral fellow in Irv Weissman's lab at Stanford, there was a lot of enthusiasm surrounding the idea that hematopoietic stem cells in the bone marrow might spontaneously transdifferentiate to produce non-blood tissues. I rigorously tested this idea and found such activity to be negligible, if present at all. That changed the course of investigation by shifting the emphasis towards defining endogenous tissue progenitor cells that carry out regenerative functions.
A second related contribution was in the skeletal muscle research area. While studying whether hematopoietic stems cells could transdifferentiate, we used parabiosis and a method I developed for single cell transplantation of hematopoietic stem cells. Those techniques were so successful for sorting stem and progenitor cells within the bone marrow that we applied them to separate stem and progenitor cells in solid tissues as well. We established a new strategy for delineating the lineage of cells in skeletal muscle.
What is currently the most pressing question in stem cell biology?
The most important challenge in stem cell biology right now is whether or not it will really deliver on the promises it has laid out. Will we actually be able to use these cells to deliver new medicines? I think we all need to keep this in mind and think about how we can translate our laboratory science to really affect peoples' lives.
