Current Research and Scholarly Interests
A major interest of the lab is the mechanism by which stem cells maintain a quiescent state, are activated to undergo proliferative expansion and differentiation, and undergo self-renewal. We focus specifically on stem cells from skeletal muscle, but study comparable processes in stem cells other mesenchymal tissue (e.g. fat) and epithelia (e.g. skin, gut, and neuro-epithelia). Our studies have focused primarily on the Notch and Wnt signaling pathways in these processes.
We have found that activation of the Notch signaling pathway is critical to the transition of muscle stem cells ("satellite cells") from a quiescent state to one of active proliferation. The regulation of Notch signaling by its inhibitor Numb appears to determine lineage progression and cell fate determination. Numb is found to be localized asymmetrically in dividing progenitor cells and may be involved in the process of satellite cell self-renewal. We subsequently found that activation of the Wnt signaling pathway occurs during muscle injury when satellite cells are proliferating. There appears to be an antagonistic interaction between Notch and Wnt signaling in activated satellite cells during this process. Furthermore, we have found that the age-related impairment of muscle regeneration is due to a decline in effective Notch signaling, manifested initially as a failure of injured muscle to up-regulate the Notch ligand, Delta. We are currently exploring further the regulation of the Notch and Wnt signaling pathways during satellite cell activation, the mechanisms underlying the transcriptional control of Delta expression, and epigenetic processes that may account for age-related changes in these pathways. Our near-term goals are to identify the key signaling processes that control satellite cell activation and lineage progression in order to enhance muscle regeneration.
Current studies are focused on the role of post-transcriptional regulation of stem cell quiescence and activation. We have discovered unique sets of microRNAs that regulate these processes and show targets are important for maintaining quiescence of promotion cell cycle entry. Ongoing studies are also addressing the role of long, intergenic non-coding RNAs in regulating stem cell function.
Our studies of stem cell aging have focused on two major areas. First, we are using microarray and next-generation high throughput sequencing to derive molecular signatures of young and old stem cells and the transcriptional and epigenetic levels. Second, we have pioneered the use of heterochronic parabiosis to study potential mechanisms of rejuvenation whereby an aged stem cell is ‘reprogrammed’ to become a young stem cell. We have been intrigued by possibility of aging being viewed as an epigenetic state, at least in part, and we are testing this hypothesis in various models in vivo and in vitro.
With regard to studies of muscular dystrophies, a major interest is the development of fibrosis and adiposis. We have intriguing data that the impairment of regeneration and the development of these pathological changes may arise, at least in part, from the conversion of muscle stem cells from the myogenic lineage to other mesenchymal lineages. These finding parallel what we have found in aged muscle as well. We are currently developing mouse models that will serve as “degeneration reporter mice” and “regeneration reporter mice” that will allow the assessment of disease progression and response to treatment non-invasively.