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

The focus of our research is to understand the cellular and molecular changes that occur within the muscle after different injuries, but 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 after orthopedic injuries. 

Our recent research has focused on understanding the interaction of the TGF-B and BMP signaling pathways and how they affect changes in the FAP stem cell population after rotator cuff injury. 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 FI. Our goal over the next five years is to expand our understanding of how these resident stem cells function in our mouse model of RC tears, and study these cell populations in patients undergoing RC repair.

Stem Cells in Rotator Cuff Injuries

Our past research identified FAP cells as the key cellular source of fatty infiltration.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. 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!
The goal over the next five years is to expand our understanding of how these stem cells function in our current mouse model of rotator cuff tears and to expand the scope of our clinical study. We hope to eventually be able to improve surgical outcomes by influencing the way stem cells in an injured rotator cuff behave after repair, that is, to use the tricks we figured out for stimulating beige fat in mice to prompt humans’ own stem cells within their rotator cuff muscles to help regenerate and improve shoulder function after injury and surgery.

Spine Injuries 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 (see above) 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 are currently looking to see whether these FAP stem cells are present in patients with low back pain and other spine problems. Finding them in human paraspinal muscle would mean 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.

Direct Muscle Injuries and Nanofibers

Using the same animal model described in the rotator cuff section above, we are looking into the use of nanofibers—specialized small fibers—as delivery agents to take stem cells and pharmacologic agents straight to the muscle defect and stimulate repair.

Ischemia/Reperfusion Injury and Stem Cells

We are also studying what happens to muscle after loss of blood (ischemia) and regaining blood flow (reperfusion). We have found that there is an increase in beige fat throughout the whole body, which may be helping the affected muscle recover. 

Treatment of Joint Contractures and Limb Immobilization

Stiff joints are a source of frustration for clinicians and patients alike. We are currently collaborating with the Desai Group on working to both treat and prevent contractures using micro and nano materials. The Desai group has found that microparticles of a specific size, shape and stiffness reduce fibroblast activation and prevent excessive collagen deposition. By harnessing these features we hope to be able to reduce peri-articular scar tissue formation, thereby improving motion and recovery after injury. 

Clinical/Translational Research

With a grant from the NIH—as well as support from the Northern California Institute for Research and Education (NCIRE) and the UCSF Department of Orthopaedic Surgery—we are evaluating how stem cells in muscle are affected by different musculoskeletal injuries including rotator cuff injuries, breast cancer, and spine injuries.  This early work will help nail down our understanding of how FAPs and other muscle stem cells are affected by injuries, and how we can use these cells to help improve muscle quality and function.