Period3 modulation of mesenchymal stem cell fate

Stanford University, Stanford CA

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Abstract

DESCRIPTION (provided by applicant): Mesenchymal stem cells (MSCs) are progenitor cells that populate the bone marrow and many other tissues, and persist into adulthood. These cells can become many cell types, including bone, muscle, and fat. The process by which this occurs in vivo is not well understood;however, the ability to bias the differentiation of stem cells to a particular cell type has obvious therapeutic value. Previous work identified that the circadian gene Period 3 (Per3) is expressed in MSCs, and in cell culture Per3 overexpression prevented MSCs from becoming fat cells. These studies will assess the impact of Per3 expression on differentiation in the intact animal, using transgenic mice. The use of cell type-specific promoters as well as Cre recombinase technology will allow for the studies of Per3 function in specific tissues or at precise developmental stages. In particular, the development and function of these tissues will be studied by qPCR for tissue-specific marker genes and histology. Furthermore, genetic lineage tracing tools will be used to determine if Per3 overexpression alters the fate selection of MSCs to a non-fat cell type, such as muscle. Such a fate selection bias or deficit in adipose mass or function might manifest as alterations to total body composition, glucose tolerance, and response to glucocorticoids, all of which will be assessed in these transgenic mice. These studies will be carried out in parallel with investigations into the mechanisms by which Per3 regulates cell fate. Overall, this project is aimed at understanding how stem cell fate choices can be manipulated, and how these changes at the cellular level impact whole animal physiology and metabolic characteristics.