Dr. Nicole Ehrhart recently shared her insights on an exciting advancement in research — and what it could mean for regenerative medicine!

Can you review what stem cells are?

NicoleIn a previous blog earlier this spring, I discussed the basis of adult stem cells and how we have used them in my lab to regenerate bones and muscles affected by cancer and limb loss. To recap, stem cells are the repair cells of the body. They travel to sites of injury in the body, and once they arrive, they secrete a whole bunch of good signals that coordinate the body’s healing response.

Remember that the molecules secreted from stem cells are the primary reason stem cells can repair tissue. Scientists aren’t 100% sure what the “magic juice” in stem cells contains, so my lab is studying those secretions and categorizing what’s in them.

A major player that we’ve found in the secretions is a tiny particle called an extracellular vesicle (EV). An EV is a very, very small packet of material surrounded by a membrane that protects the contents, or “cargo.” So, EVs are packets designed to shield the EV cargo from breaking down before it can do its job at the site of an injury in the body.

What makes extracellular vesicle therapy different than stem cell therapy?

Nicole: One key difference between stem cell therapy and EVs is that we don’t need the entire stem cell to carry out EV therapy. Stem cells can secrete EVs into the bloodstream or tissue, and those little, tiny vesicles can find their way to a site of injury, similar to the way a parent stem cell would have done, and that smaller EV packet can then do exactly the same thing in delivering healing properties to an injury.

A benefit of this is that they don’t have to deliver a live cell to a patient, which can be difficult to handle in the lab and can only be stored using specific conditions to keep the cells alive and healthy enough to do their job. Stem cells are not abundant in adult tissue; they’re few and hard to find, and once removed from the body, it’s harder for stem cells to divide, which makes it difficult to grow large quantities of adult stem cells for therapies. So, instead, we can collect these tiny EVs from parent stem cells and purify them in a way that we couldn’t do with stem cells before.

Still, EVs mimic the same kinds of good repair effects that the stem cells did to begin with. This is what we would call a cell-free therapy. Once we collect enough EVs from the stem cell secretions, we can enrich them with other good ingredients to target a specific disease to treat.

This is why I call this work “Regenerative Medicine 2.0,” because it’s the next step after stem cell therapies.

What diseases or conditions are you targeting with extracellular vesicles?

Nicole: So, you might recall that my lab is most interested in stem cells that are found in our connective tissues (muscles, tendons, fat, and bones), which are called mesenchymal stem cells, or MSCs. And one natural effect of aging is sarcopenia, or the loss of muscle mass, which starts in our late 30s and 40s. It is just a natural side effect of aging: as we age, our muscle mass decreases. For example, people who are skeletally thin at the end of life, much of that is due to sarcopenia, but we know that exercise can slow the rate of sarcopenia quite a bit. That’s one reason exercise is so good for us and is a recommended tip for healthier aging.

But sarcopenia can also happen in other circumstances, like starvation, advanced cancer, tumor surgery, and other conditions – or if we’ve been injured and we’re no longer active. For instance, think about a football player who gets a knee injury and must be on crutches. If you measure his thigh muscles on the side of the ligament injury, you’ll find that they’re much smaller than the other side because he’s not exercising that leg and can’t while recovering.

So, my lab is interested in thinking about EV therapy as a way to prevent the slow decline of muscle during aging, but also as a way to regenerate muscle after a tumor surgery or in cancer patients. In essence, we are finding ways to optimize the cargo of the EVs specifically designed to help the body regenerate muscle.

What kind of methods go into creating an EV designed to help muscle regenerate?

Nicole: So, this is really interesting! First, we isolated the stem cells from muscle tissue. And then, we “exercised” the stem cells outside the body, meaning we put the MSCs on a special bioreactor. We found that the cargo of the EVs from those exercised stem cells was enriched for molecules and growth factors that promote muscle regeneration. We then put them back into the body at a severe muscle injury site. We’ve been able to show in the laboratory that the EVs remained at the site of the injury and helped the muscle to heal.

What’s fun about this whole concept is: let’s say that you, dear reader, are an elite athlete, but you need surgery, which means you’re going to be on bed rest. But my goodness, you’ve got the Olympics coming in six weeks! How can we prevent your body from losing muscle mass and fitness over time? Could we just grow your stem cells in a petri dish, exercise your stem cells on a bioreactor, collect the things they secrete (which are these EVs), give them back to you, and maybe prevent the muscle loss that would have occurred? Or if you’ve had tumor surgery that required removal of muscle, could we get that muscle to repair itself more completely?

Consider another scenario in an aging adult: could we undergo EV therapy periodically throughout our lives to give ourselves a little boost, or a refurbishing of our muscle mass, if you will, to make our muscles act 10 years younger? Imagine preventing frailty in older adults by treating or preventing age-related muscle loss. That would make a huge difference in the lives of many older individuals, and maybe we could prevent other consequences of frailty, such as more frequent falls, more severe injuries when you do fall, or hospitalizations.

Now, I want to caution that EV therapy is still experimental and may not mimic all the benefits of exercise, such as improved cardiovascular health, improved brain health, or reduced risk of disease. This is purely from the perspective of skeletal muscles, but we’ve been successful! And that’s what’s fun about this research — we don’t know exactly where it will take us, but I have a feeling it will be a huge advancement.

Are there other examples of where extracellular vesicle therapy is being used?

Nicole: One of the things that is interesting about EV therapy and regenerative medicine is that they’re extremely new, so we’re talking about science that is so cutting edge that many have no idea what extracellular vesicles are. However, there are a few studies in companion animals, specifically horses and dogs, where EVs have been used to treat specific diseases. Right now, the studies are so small, and they’re not very well controlled or designed yet. It’s a little reminiscent of the old Wild West of stem cells where we’ll just try them in all sorts of applications. And I want to avoid the mistakes the field made with stem cells 20 years ago. We really want to think about how to design studies with better efficacy. What’s the right dose of EVs? What’s the right disease for EV therapy? There are currently more questions than there are answers. What we do know, based on a few studies, is that EV therapies seem to be safe. But we want to be very intentional about how we study these vesicles so that they’ll be used in the most effective ways.

Dr. Nicole Ehrhart holds the Ross M. Wilkins, M.D. Limb Preservation University Chair in Musculoskeletal Biology and Oncology at the Colorado State University Flint Animal Cancer Center.