Mesenchymal stem cells and skeletal development
Research in my lab is focused on development and postnatal activity of the skeleton. Osteogenic, chondrogenic, adipogenic and myogenic cells develop from a pool of mesenchymal stem cells and primitive progenitor populations in bone and bone marrow. One aspect of our work addresses both how to characterize and how to control self-renewal, fate choice, proliferation and differentiation of the stem, progenitor and more mature precursor populations so as to map the developmental hierarchies underlying mesenchymal lineages. To do this, we are assessing the ability of endogenously produced or exogenously supplied hormones, cytokines, and growth factors to influence progenitor proliferation, self-renewal and differentiation to dissect deterministic versus stochastic pathways of mesenchymal cell development. We have acquired evidence for differentiation stage-specific regulatory pathways and for dose-, and time-dependent biphasic effects of many regulators of interest. We are also interested in the regulatory and developmental basis of the phenotypic heterogeneity we have documented in post-proliferative mature cell phenotypes in the developing and mature skeleton.
Amongst regulators of the highly dynamic postnatal skeleton, we are currently studying the family of estrogen receptor-related orphan nuclear receptors, and have developed novel gain-of-function and loss-of-function transgenic mice to delineate the functional role of these transcription factors in health and disease of bones and joints. We are also using genome-wide chemical (N-ethyl-N-nitrosourea; ENU) mutagenesis in mice to identify novel genes and mutations that regulate formation and turnover of the skeleton and are characterizing their cellular and molecular modes of action in the developing and postnatal skeleton.
My laboratory has developed many transgenic and knockout mouse models with skeletal anomalies, primary cell culture models for mesenchymal cell differentiation, assays for enriching stem and progenitor populations and dissecting developmental transition points, and tools for analysing skeletal cells and their fate including fluorescence-activated cell sorting (FACS), colony assays, gene expression profiling, immunocytochemistry and imunnohistochemistry, in situ hybridization of embryonic and adult tissues and cells, Western blotting, single cell assays and other state-of-the-art cell and molecular biology techniques. By this multi-faceted model organism, developmental, cell and molecular biological approach, we are advancing understanding of normal development and diseases of the skeleton.