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BMP induced migration of bone precursor cells – an in vitro and in vivo study

Prof. Knaus (first supervisor), Prof. Lauster (second supervisor); Free University Berlin and DRFZ

The BMP family of growth factors comprises over 20 ligands belonging to the Transforming Growth Factor ß superfamily. Recombinant BMP2 and BMP7 are clinically approved tools for regenerative therapies such as the treatment of open tibial shaft fractures and for tibial nonunions. Today the coating of implants with BMPs seems to be a promising strategy to improve bone healing.
BMPs differ in their receptor affinities and vary in their potency to induce a subset of BMP signalling pathways, e.g. the canonical Smad pathway, MAPK and PI3K pathways (Nohe A et al. J Biol Chem, 2002).
These pathways have distinct cellular functions with sometimes opposing effects. Among them, the best characterized pathway is the Smad pathway which is driving bone precursors such as mesenchymal stem cells to differentiation (Sieber et al., CGFR, 2009). Our current understanding to the BMP-induced MAPK and PI3K pathways is that they might contribute to bone development in a different manner.
Bone precursor cells need on one hand to differentiate but also to migrate towards the site of injury and/or bone remodelling. BMPs act as chemoattractants to induce directed migration of mesenchymal precursor cells, osteoblasts and chondrocytes (Lee DH et al., Tissue Eng 2006; Granero-Molto F et al., Stem Cells, 2009; Mishima YJ et al., Orthop. Res, 2008). BMP2 expression in bone precursors correlates with callus initiation, indicating a positive regulatory feedback loop between BMP-induced cell migration and autocrine secretion. Latest research points towards BMP-induced non-transcriptional responses, including immediate changes in actin cytoskeleton remodeling via the regulation of Rho GTPases (Gamell CJ et al., J Cell Sci 2008).
In the PhD project we aim to proof different BMPs for their chemoattractant potential and tissue repair capacity. We will investigate the migratory behaviour of cells using BMP treatment in combination with other growth factors.
The goal will be to establish growth factor cocktails to improve both the differentiation as well as the migratory effects of bone precursor cells. This will then be adjusted to age dependent differences in mesenchymal stem cell populations from different patient donors (personalized therapeutic approaches). We will use state of the art life cell imaging and a combination of new tissue culture techniques for cell polarization as well as tools for investigating the migration of cells in vitro and in vivo.
For this we would require students with some expertise in imaging and cell culture.