Saturday’s third lecture session was Toward Optimized Skeletal Muscle Regeneration Across the Lifespan: Measuring and Manipulating Stem Cell Function and given by Fabrisia Ambrosio.
Fabrisia began by kindly reviewing Mauro’s muscle regenerative cascade: 1. myofiber (muscle cell) stem cell “hypernation” as it works along, doesn’t need repair 2. injury 3. stem cells multiply, run to injury site 4. stem cells fuse together and align their nuclei along the injury site 5. stem cells grow up and become “adult” myofibrils, losing their own nuclei. That’s the ideal anyway. Sometimes in step 5 the stem cells don’t become myofibrils, but instead become scar tissue or fat. Which is not good for regeneration. This happens in all people some though. This is where soreness comes from: the stem cells have become tiny scars that don’t work like normal muscle tissue leading to pain. You have to break up those scars with a variety of treatment options and tell the body to try again and “do it right this time!”
Fabrisia’s hypothesis was it additional stem cells are transplanted to an acute injury site, would there be better myofibril formation? There are several barriers to this hypothesis. First of all, just getting the donor stem cells to survive is hard. The donor stem cells like to stick together; they don’t like to play with host’s stem cells and tend to just hang out at the injection site instead of running off to do their job at the injury. Then sometimes they blindly follow along with the hosts’ cells and become scar tissue instead of myofibrils. And even if they do become myofibrils, often no functional improvement occurs, so what was the point?
Now we need to figure out what’s going wrong here. Is the stem cell “seed” bad or the hosts’ “soil”? Several things that are hypothesized to improve the “soil” are preconditioning the host’s muscle, injecting some growth factors with the stem cells, gene therapy, having a scaffold (usually made from animal tissue) to show the cells where and how to build, or mechanical stimulation. The last– mechanical stimulation– is where therapy might come in as exercise creates mechanical stimulation. Fabrisia specifically looked at running injured mice on a treadmill. This hypothesis seemed to work with a mouse that had been injured. The mouse showed improve stem cell survival, improved stem cell migration, less scar tissue formation, but not really improved function.
Can we expound on this hypothesis to apply it to disease, such as Duchenne Muscular Dystrophy (DMD)? So they injected a mouse with DMD and added e-stim this time (too much exercise further destroys the muscles in DMD, so didn’t want to make it worse. Chose different mechanical stimulation.) The mouse showed increased dystrophin (the molecule that breaks down and causes symptoms of DMD) and improved recovery after fatigue (a hallmark symptom of DMD).
The application for the future: Could stem cell transplant + physical therapy = improved functional outcomes? Or how about adding one of those bioscaffolds? What would be the optimal dosage (FITT principle) to apply to these folks? How is the hosts’ tissue altered physiologically? How could mechanically loading the tissues change the outcomes? Good questions all.
Fabrisia pointed out that others are already looking into this, citing a recent article in the Scientist called “Cellular Rehab,” who aren’t therapists and that if we want our opinions in on this topic on the forefront, we better jump in quick. She suggested looking into the Alliance for Regenerative Rehabilitation Research and Training, if you’re interested.