SMC development, lineage and disease
Our work combines the fields of stem cell biology and vascular biology to provide new insights into vascular smooth muscle cell development and novel treatments for vascular diseases. We have developed in vitro systems using murine and human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells in which pure populations of mature contractile vascular SMCs may be generated.
These and other model systems are currently being used to investigate how SMCs and their precursors initially develop from multipotent cells and how perturbation of developmental mechanisms may contribute to disease. The group’s focus is on the role of the myogenic transcription factor, myocardin and transforming growth factor (TGF)-β and Notch signalling as well as other transcription factors and signalling cascades that interact with these pathways. In addition, we are determining whether SMCs of different lineages respond differently to atherosclerotic mediators, whether these differences account for some of the regional heterogeneity in atherosclerosis development, and the underlying mechanisms responsible for the differential response.
Modelling genetic diseases using patient-derived iPSCs
A major focus of the group is to use our established in vitro system and patient-derived iPS cells to model genetic disorders in which there is a key SMC phenotype. Marfan syndrome, in which aortic SMC loss and matrix breakdown lead to aortic dissection, is the exemplar for this approach. Other conditions with a significant SMC phenotype that we are also modelling using this approach include Loeys-Dietz syndrome (TGFBR mutations) and CADASIL (NOTCH3 mutation).
Myocardin as a key regulator of vascular disease
We have carried out the first gain- and loss-of function studies in vivo to identify a new role for Myocardin in regulating the vascular injury response and atherosclerosis. We have delineated some of the molecular mechanisms by which myocardin regulates SMC biology in these conditions and hypothesise that myocardin is a ‘guardian’ of vascular health. Further studies are under way to clarify the underlying mechanisms in more detail and to determine whether modulation of myocardin represents a novel approach to treating vascular diseases.