Detailed project information

Human mesenchymal stem cells (hMSCs) are essential for regeneration of many tissues in the adult body. They can be cultured in vitro and, depending on the stimulus, can differentiate into distinct lineages, including bone, cartilage or fat. Differentiation of hMSCs requires addition of dexamethasone and is strongly enhanced by bone morphogenetic proteins (BMPs). Importantly, my recent data show that the nuclear proto-oncogene c-Myc is a potent commitment factor in differentiation of hMSCs, and acts synergistically with BMPs. In particular, lentiviral overexpression of c-Myc strongly enhanced osteogenesis induced by dexamethasone+BMP-2. Moreover, DNA binding sites for c-Myc and Smad1/5/8, transcriptional regulators of canonical BMP signalling, co-exist and are over-represented in promoters of genes regulated during osteogenesis. Based on my findings I hypothesize that c-Myc and the BMP pathway enhance each other?s activity to induce target genes that are relevant for lineage-dependent differentiation of hMSCs. Aim of my studies is to reveal the mechanisms by which c-Myc and BMP-2 synergize to promote differentiation. Therefore, I will investigate whether c-Myc and BMP-Smads physically interact as a transcriptional mechanism of synergy. In addition, I will study whether BMP-2, via casein kinase 2, activates c-Myc by phosphorylation as a post-translational mechanism of cooperation. Next, I will perform transcriptomics studies to identify and validate target genes that control osteogenesis downstream of cooperative c-Myc/BMP-2 signalling. Finally I will establish the role of c-Myc/BMP-2 signalling during adipogenesis and chondrogenesis and reveal the transcriptional co-regulators that cooperate to specify lineage-determination. I expect that these studies will provide insight into the mechanisms by which c-Myc and the BMP pathway functionally cooperate and control hMSC fate decisions. Myc and BMPs are pivotal regulators of many biological processes, including stem cell plasticity, development, tissue homeostasis, and disease pathogenesis, and therefore these studies are expected to have great impact for cell biology in general.

Articles

• LS Sleumer, RI van Ravestein-van Os, I de Grijs, C Gilissen, EP van Someren, E Piek, EJ van Zoelen, L Heuver, S Bauerschmidt, JM Hendriks, KJ Dechering, JR de Haan (2010). Osteo-transcriptomics of human mesenchymal stem cells:. Accelerated gene expression and osteoblast differentiation induced by vitamin D reveals c-MYC as an enhancer of BMP2-induced osteogenesis.. Bone. pp. 613-627. ISSN 8756-3282.