Based in part on their prior VA Merit Grant, Brian Feeley and Xuhui Liu, along with collaborators within the UCSF Department of Radiology and Orthopedic Surgery, were awarded a 4 year, 1.2 million dollar award to study the mechanisms behind FAP stem cell differentiation in patients with rotator cuff injuries.  The research will allow them to study FAP stem cells obtained from patients at the time of surgery, and evaluate both their gene expression patterns on a single cell level, as well as look at how these cells may be leveraged to promote muscle regeneration.  

Rotator cuff (RC) tears are the most common upper extremity injury, with over two million Americans

seeking medical attention annually. With the increased age of our veterans’ population, RC tears are

becoming a vital health issue for the VA patients. Secondary muscle degradation following tears,

including atrophy and fatty infiltration (FI) are critical factors that directly determine the clinical

outcome of patients with this injury. Muscle residential fibro/adipogenic progenitor (FAP) cells have

been found to be the major cellular source of fat in RC muscle after massive tendon tears. We recently

discovered that these cells represent a heterogeneous cell population capable of both regenerative and

pathologic responses to muscle injury. Importantly, FAPs can differentiate into a beige adipose tissue

(BAT) phenotype that may have a role in promoting muscle recovery and regeneration in chronic injury

states. However, at this time, no studies have evaluated factors that influence the fate of FAPs in

human cuff tears, nor what FAP regenerative capabilities could be in clinical scenarios such as rotator

cuff repair. Clinically, both patient age and size of the rotator cuff tear have been found to be

independent factors that associate with poorer muscle quality and worse patient outcomes. However,

the interplay between patient and rotator cuff tear size and their influence on muscle stem cell

proliferation, differentiation, and regenerative capabilities is not known at this time. To address this

problem, we will perform the first large-scale clinical study evaluating FAP phenotypic properties in

patients with rotator cuff tears. Expanding on our promising mouse studies that show FAPs are capable

of stimulating muscle regeneration, we will perform a rigorous set of studies that will determine the

regenerative capabilities of human FAPs in this clinically relevant scenario to confirm our hypothesis

that the ability of FAPs to promote healthy muscle regeneration is dependent on the size of the tear and

age of the patient due to changes in FAP gene expression. By the end of this study, we will understand

how clinically important factors (age, tear size) affect the degeneration and regeneration potential of

human FAPs, which should provide critical information on how these endogenous stem cells can be

leveraged to improve precision guided patient outcomes with targeted therapeutic strategies in the near

future.