Pharmacological Regulation of Adult Stem Cells: Chondrogenesis can be Induced Using A Synthetic Inhibitor of the Retinoic Acid Receptor

¹ University of Bristol Academic Rheumatology, Department of Clinical Science at North Bristol, University of Bristol, UK.

^* To whom correspondence should be addressed. E-mail: A.Hollander{at}Bristol.ac.uk.

	Abstract

Conventional methods for regulating the differentiation of stem cells are largely based on the use of biological agents such as growth factors. We hypothesise that stem cell differentiation could be driven by specific synthetic molecules. If true, this would offer the possibility of screening chemical libraries in order to develop pharmacological agents with improved efficacy. In order to test our hypothesis, we have determined which, if any, of the nuclear receptor superfamily might be involved in chondrogenesis. We used fluorescence activated cell sorting (FACS) as well as quantitative PCR to study expression of a range of nuclear receptors in the undifferentiated mesenchymal population and after growth-factor driven differentiation of these cells to chondrocytes. In this way we identified retinoic acid receptor (RAR) as a potential pharmacological target. A low molecular weight synthetic inhibitor of the RAR and receptors was able to induce chondrogenic differentiation of mesenchymal stem cells derived from osteoarthritis patients, in the absence of serum and growth factors. Furthermore, the pathway is independent of SOX9 upregulation and does not lead to hypertrophy. When mesenchymal cells were seeded on to polyglycolic acid scaffolds and cultured with LE135 there was a dose-dependent formation of cartilage, demonstrated both histologically and by biochemical analysis of the collagen component of the extracellular matrix. These results demonstrate the feasibility of a pharmacological approach to the regulation of stem cell function.