Developing novel injury and repair models
Stem cells found within rotator cuff muscle can be stimulated into fibrotic tissue (red) or fat tissue (green) depending on the stimulus. Researchers are evaluating tools to improve the function of these cells to improve outcomes after rotator cuff repair.
Developing novel injury and repair models
Developing novel injury and repair models

Muscles—the forgotten part of musculoskeletal medicine and orthopedic research!

Much of orthopedic surgery research focuses on cartilage, ligaments, bones, and tendons.  However, muscle is the largest organ in the musculoskeletal system, and is a dynamic organ that is critical in maintaining the health of athletes and weekend warriors.  The focus of our research is to understand the cellular and molecular changes that occur within the muscle after different injuries, particularly rotator cuff tears. We have developed novel injury and repair models to study the acute and chronic effects of rotator cuff injury on the important signal transduction pathways that govern muscle cell size and stem cell fate within the muscle.  We also focus on understanding how muscle injury patterns affect the stem cell populations within the muscle (satellite cells, FAP cells) in an effort to determine treatment strategies that would improve muscle function following orthopedic injuries.
Our recent research has focused on understanding the interaction of key signaling pathways and how they affect changes in the FAP stem cell population after rotator cuff injury--particularly the TGF-B and BMP pathways. We are currently evaluating the relationship between these signaling pathways, beige adipose tissue (BAT), and FAP cells since both stem cell populations share similar markers of expression.  BAT has an important role in energy balance and may produce local growth factors such as IGF-1 that can promote a healing environment for muscle. The emergence of BAT is of particular importance in RC injury given the clinical significance of fatty infiltration and atrophy in muscle as we age or get injured. We are taking advantage of the amazing core facilities at UCSF to study these stem cells at a single-cell transcriptomic level using single-cell RNA sequencing and spatial transcriptomics in animal models and clinical samples of injury and repair. Our goal over the next five years is to expand our understanding of how these resident stem cells function in our mouse models of RC tears and develop strategies to improve outcomes after rotator cuff repair and other chronic injury states.  We are always looking for new and exciting ideas, techniques, and collaborators!

Stem Cells in Rotator Cuff Injuries

Our past research identified FAP cells as the key cellular source of fatty infiltration, which we subsequently confirmed in patients with rotator cuff tears. Then we started to look at how FAP cells decide whether to stay classic white fat or differentiate to beige fat and aid in muscle regeneration. We focused on two signaling pathways (TGF-B and BMP) to see whether they affect changes in the stem cell population after rotator cuff injury. To do so, we developed a mouse model that simulates human cuff tears and involves tiny surgeries that mimic human rotator cuff repair. Now, we are transplanting different cells and administering pharmacologic agents (medicines created for other purposes) into the mice and watching what happens. We are also evaluating exactly how beige fat promotes muscle regeneration, from the direct expression of different proteins, to the production of exosomes. Everything we’ve found so far suggests that we can influence FAP stem cells and increase regeneration in animal rotator cuff muscle.
We recently began clinical studies looking for FAPs (and other stem cells) and evaluating their activity in human rotator cuff tear patients. We want to know if there is a source of stem cells already within the rotator cuff muscle that can be used to help regenerate muscle after cuff repair. Early results suggest an abundant cell source already present in rotator cuffs that can be stimulated to help decrease muscle atrophy and stimulate muscle regeneration!

Building Better Preclinical Models

It’s challenging to study how humans function and respond to injury in animal models.  Mice aren’t humans, and they behave quite differently.  We began our research by developing models that closely mimic the muscle atrophy and fatty infiltration in the rotator cuff that we see in people.  This model has become the standard to study muscle degeneration.  We then worked on a better chronic injury and repair model, since most rotator cuff repairs are done in patients with months to years of pain and limited function. The next step is to use AI-based resources such as DeepLabCut to better study how mice behave in upper extremity tasks. In our recent study, we developed a ‘string pull’ task to show that the mice behave differently after rotator cuff injury compared to their normal arm.  What is really interesting is when we give patients the same task, they have motion patterns that are very similar to the mice, suggesting that we can use this tool to study ways to improve function in mice and immediately translate the findings into patients.

The Spine, Spinal Cord, and Muscle Stem Cells

One of the critical factors influencing the development of low back pain, as well as the ability to recover from spinal surgery, is the quality of muscle around the spine. Paraspinal muscle in the low back can atrophy and degenerate with classic white fat deposits in the muscle.
In animal studies, we found that the FAP stem cells that are present in the spine are very similar to the FAP cells within rotator cuffs. Our research on rotator cuff tears shows that these FAPs are more likely to degenerate into white adipose tissue and may be the key culprit for muscle degeneration. It also suggests that with the right stimulus they could be the key to stopping and even reversing that process.
We have also found that these FAP stem cells are present in patients with low back pain and other spine problems. Finding them in human paraspinal muscle means a local stem cell source that very well may be used to stimulate muscle regeneration in patients with back pain and those recovering from spinal surgery.
The next questions we want to answer focus on how the central nervous system reacts to chronic muscle injury, either from the low back muscles or from the rotator cuff.  Since patients react so differently to similar types of rotator cuff tears, we hypothesize that there may be neurologic changes at the neuromuscular junction or in the central nervous system itself.  We are collaborating with neuroscientists at UCSF to determine if there are changes in the central nervous system in chronic low back pain or rotator cuff injury and if treatments targeted at this could improve outcomes.

Hydrogel Research

Using the same animal model described in the rotator cuff section above, we are looking into the use of hydrogels—specialized small fibers—as delivery agents to take stem cells and pharmacologic agents straight to the muscle defect and stimulate repair.  Working with Dr. Kevin Healy and his colleagues at UC Berkeley, and funded by a CIRM research grant, we are investigating if hydrogels can deliver stem cells and their products into muscle to improve outcomes.

Ischemia/Reperfusion Injury and Stem Cells

When the blood supply to a muscle is disrupted, it loses oxygen and becomes injured.  As blood supply is restored (reperfused) there is a secondary injury to the muscle that is actually much more severe (reperfusion injury).  While this can lead to severe muscle damage and severe systemic illness, small amounts of ischemia and reperfusion can actually be helpful.  This is called ‘Preconditioning’ and is the basis of the ‘Blood Flow Restriction’ physical therapy technique.  In a recent study, we found that preconditioning is related to inducing FAPs into a beige-like phenotype.  In treatment with pharmacologic therapies, we found that we could simulate preconditioning.  We are currently looking at exactly how this works in work supported by a grant from the VA Healthcare System.

Clinical/ Translational Research

More studies, ideas, and hypothesis are always being tested. If you have an idea related to these studies, contact us, and let’s set up a time to talk about your ideas around muscle injury and recovery, translational orthopedic surgery research, and improving the health span of patients with musculoskeletal problems.