Research

Rejuvenation of aged muscle stem cells and tissues

We have discovered that as people age, their muscles accumulate increasing amounts of a protein called 15-PGDH that breaks down a natural inflammatory molecule, Prostaglandin E2 (PGE2), critical to muscle repair after injury. Our data show that reducing the amount of 15-PGDH or using a drug to block its activity in old mice increases their overall health. Treated old mice are able to run longer distances on a treadmill, their muscles are larger, and they are stronger. Blocking 15-PGDH also stimulates muscle stem cells, rejuvenating the muscle’s ability to heal after injury. Conversely, increasing 15-PGDH levels in young mice shrinks and weakens their muscles, mimicking the effect of years of aging in 1 month. Our goal now is to understand how changing 15-PGDH abundance causes these effects and if other tissues are similarly impacted. PGE2 helps regulate cell growth and energy production by rejuvenating mitochondria, the cell’s energy source. Read More

 

Regulation of muscle stem cells in regeneration

Aging is characterized by a decline in tissue function and regenerative capacity. Sarcopenia, also known as age-dependent loss of skeletal muscle mass and strength, is a major pub-lic-health problem that affects 15% of the elderly, leading to loss of mobility and diminished quality of life. Age-related muscle loss is paralleled by a loss in the function of muscle stem cells (MuSCs), key players in muscle homeostasis and regeneration. However, the mechanisms responsible for age-associated MuSC dysfunction remain elusive. Two major barriers to gaining mechanistic insights into MuSC aging are the heterogeneity of the aged MuSC population, which renders standard bulk analysis ineffective, and the lack of tools to resolve this heterogeneity, underscoring the need for single-cell studies. We previously demonstrated that aged MuSCs are a heterogeneous population comprised of functional and dysfunctional subsets. This key observation suggests a therapeutic strategy to regenerate muscle - boosting the activity of resilient functional MuSCs. We are exploring this possibility using a specific cell surface marker and a series of innovative single-cell technologies required to resolve MuSC subsets. Read More

Bioengineering biomaterials to assess signaling in response to mechanosensing

Cells function as components of a complex, ever-changing tissue milieu. How cells respond to changes in their microenvironments, such as tissue stiffening, in real time, is a fundamental biological question. Aging is often accompanied by increased tissue stiffness or fibrosis. Fibrosis alters the behaviour of cells in the aged tissue which, as a consequence alters the crosstalk between various cell types in the aged muscle niche. We are developing dynamic hydrogel biomaterials that enables real time measurement of cellular dysfunction to determine how progressive fibrotic stiffening detrimentally impacts cell fate.  We are also using tissue engineering techniques to develop a physiologically active niche to identify molecular targets that regulate muscle stem cell quiescence in aged tissue. Read More

Telomere dysfunction in cardiomyopathy in Duchenne and Becker Muscular Dystrophy

Duchenne's Muscular Dystrophy (DMD) and Becker Muscular Dystrophy (BMD) patients exhibit severe muscle degeneration and often die from dilated cardiomyopathy that manifests later in life. This delayed onset strongly argues for a mechanism tied to the continuous contractile stress from the lack of dystrophin, which leads to progressive myocardial fibrosis. We have previously demonstrated an unexpected correlation between dystrophin deficiency and telomere shortening in cardiomyocytes in the pathogenesis of DMD, both in mouse and human. This correlation extends to other genetic dilated cardiomyopathies, suggesting it is a novel, broadly applicable, fundamental cellular mechanism resulting from altered cellular environmental sensing. Our finding is highly controversial, as telomere shortening has previously been strictly linked to cell division, and cardiomyocytes do not divide. We are exploring the mechanisms that underlie this phenomenon, as well as testing the efficacy of DMD and BMD gene therapeis in cell culture and rodent disease models. Read More