Rejsemidler fra Lundbeckfonden: Early decisive events in mesenchymal stem cell differentiation

Projekter: ProjektForskning



Mesenchymal stem cells (MSC) constitute a population of multipotent cells found in many different organs, where they play an important role in tissue regeneration and homeostasis. They give rise to mesoderm-type cells such as osteoblasts, white and brown adipocytes, chondrocytes and myocytes, and this high degree of plasticity makes them attractive targets for e.g. stem cell therapies. Differentiation into these various lineages requires a complex sequence of transcriptional events that reprograms the genome and switches on the set of genes characteristic of the different cell types. The overall aim of this project is to obtain comprehensive genome-wide insight into transcriptional regulators and networks of regulators implicated in the early decisive events distinguishing the osteoblast and adipocyte lineage of human MSC.
Starting from undifferentiated human mesenchymal stem cells we will use genome-wide approaches to map changes in the chromatin structure during differentiation to osteoblasts and adipocytes. This information will be combined with other chromatin signatures to map at a genome-wide level putative key regulatory regions involved in directing the transcriptional events
distinguishing the early stages of the osteoblast and adipocyte lineages. Based on bioinformatics interrogation of the DNA sequence of these regions we will predict transcription factors, or families of factors, that may bind to the regions and potentially play a role in the conversion to the respective lineages. The importance of the factors will be investigated by loss-of-function and
gain-of-function experiments. For the most important candidate factors we will determine their:
1) genome-wide binding profile;
2) molecular mechanisms of action including cross-talk with other factors; and 3) the regulation.
Effektiv start/slut dato01/01/201331/12/2014