Vujovic, S.; (2006) Transcriptional profiling of mesenchymal stem cells, undergoing chondrogenesis, and mesenchymal tumours. Doctoral thesis , University of London.

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Abstract

Mesenchymal stem cells (MSC) represent an adult stem cell population isolated from the bone marrow with the ability to differentiate down various mesenchymal lineages including cartilage. The development of cartilage is a complex multiphase process regulated by the interplay of factors such as cell density and oxygen availability as well as many signalling pathways including TGFp, MAPK, FGF and Wnt. Using microarrays, the temporal transcriptional changes occurring in the in vitro MSC chondrogenesis model were analysed. The results obtained support the validity of the MSC model system for the study of chondrogenesis, as genes known to play a role in the process such as collagens 2, 9 and 11, aggrecan and the transcription factor Sox9, are expressed in the chronological pattern expected. Genes were also identified that had been previously noted to be expressed in limb development but whose role in chondrogenesis remains unknown, as well as a group of novel factors not previously associated with chondrogenesis. Hes1 and Hey1, the targets of Notch signalling were both found to be upregulated early, and their role in chondrogenesis was investigated by inhibiting Notch signalling. Abolishing the expression of Hes1 and Hey1 had a deleterious effect on the accumulation of the chondrogenic matrix, indicating that these transcription factors are implicated in chondrogenesis. Microarray analysis was also used to compare the expression profiles of a broad range of mesenchymal tumours, resulting in the identification of factors specific to each. The brachyury gene was found to be specifically expressed on chordomas, a tumour derived from notochordal remnants often misdiagnosed for a chondrosarcoma. Immunohistochemistry was performed using a polyclonal antibody to this molecule and was found to distinguish chordomas from over 300 other lesions, including a wide variety of chondroid neoplasms. Brachyury is therefore a specific marker for chordomas, and can be exploited for diagnostic purposes.

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