Research of the molecular mechanisms concerned with bone marrow homing of human mesenchymal stem cells.

Mesenchymal stem cells (MSC) form a population of undifferentiated bone marrow cells. First, they are unspecialized cells that renew themselves through cell division. The second is that they can differentiate into (non-hematopoietic) specific cell types. MSC can differentiate into bone, tendon, cartilage, stroma, muscle en neural cells. MSC have the capacity to support in vitro the growth of primitive hematopoietic stem cells by secretion of different kinds of cytokines which will stimulate the proliferation and differentiation of the hematopoietic stem cells. In animal models was shown that intravenous injected MSC home to different organs, i.e. bone marrow, and differentiate in situ. Following these observations, it is possible to use MSC on a therapeutical base for repair of the bone marrow micro-environment after damage by myeloablative chemotherapy, for the correction of acquired or congenital diseases in bone, muscle or cartilage or as target cells by gentherapy for congenital or malign disorders. An efficient homing of intravenous injected mesenchymal stem cells to the bone marrow contents that these cells dispose of mechanisms which permit transendothelial migration. In analogy with the extravasation of normal leukocytes, it can be accepted that the migration mechanism of mesenchymal cells takes place in different stages, whereby the cells first bind to the endothelium and then migrate through it (incl. basement membrane). In this research project we study the homing mechanisms of in vitro expanded MSC, and in particular the specific role of adhesion molecules, chemokines and metalloproteinases in the extravasation process.