Regulation of Mesenchymal Stem Cell Differentiation by Chemerin/CMKLR1

Mesenchymal stem cells (MSCs) are multipotent stromal cells with the ability to differentiate into several specialized cell types including bone forming osteoblasts and fat storing adipocytes. During MSC differentiation, global gene expression profiles change such that genes associated with multipotency are repressed and those required for the specialized cell phenotype are activated. This requires the coordinated action chromatin remodeling enzymes such as histone acetyltransferases/deacetylases (HATs/HDACs). These proteins also affect the function of key transcription factors associated with specific lineages through post-translational modification. We have identified a secreted protein, chemerin, which exerts a powerful influence on MSC differentiation by activating a cell surface receptor termed chemokine-like receptor 1 (CMKLR1). We have shown that blocking chemerin/CMKLR1 signaling enhances MSC osteoblastogenesis and abrogates MSC adipogenesis. We have also found that this results in increased activity of several HDACs coincident with changes in the expression and activity of key effectors of adipogenic and osteoblastogenic signaling. The long-term objective of our research program is to identify the mechanisms by which chemerin/CMKLR1 signaling regulates MSC differentiation. As a part of achieving this objective, we will pursue the experiments proposed herein to address the global hypothesis that chemerin/CMKLR1 impacts the function of key osteoblastogenic and adipogenic signaling pathways in MSCs by regulating the expression and activity of histone/chromatin modifying enzymes. Specifically, we will determine: (1) Changes in the transcriptosome of MSCs associated with chemerin/CMKLR1 modulation in the context of normal cell growth and differentiation (adipogenic and osteoblastogenic). (2) The impact of chemerin/CMKLR1-mediated changes in HDAC/HAT activity levels with respect to the stability, function and protein-protein interactions of key effectors of adipogenic/osteoblastogenic signaling in MSCs. (3) The impact of chemerin/CMKLR1-mediated changes in HDAC/HAT activity levels with respect to promoter accessibility and transcription factor binding to genes encoding key effectors and targets of adipogenic/osteoblastogenic signaling in MSCs. These novel studies will advance our fundamental understanding of the mechanisms underlying the role that chemerin/CMKLR1 plays in MSC differentiation. We and others have shown that chemerin/CMKLR1 signalling influences the function and development of other cell types involved in a variety of biological processes including muscle development, tooth and bone formation as well inflammation. Thus, these studies have a broad relevance and the potential to impact and inform several areas of research in cell differentiation and animal development.