Chemotaxis and chemorepulsion in hematopoietic (stem) cells

Project leader: Paula van Hennik PhD

The chemokine Stromal Cell Derived Factor-1 (SDF-1/CXCL12) and its receptor CXCR4 are critical for homing of hematopoietic stem cells (HSCs) to the bone marrow after transplantation, and they are also relevant for tumor cell metastasis and inflammation. Our goal is to unravel the signaling involved in the regulation of chemokine-induced migration in order to facilitate manipulation of the migratory capacity of cells. This is relevant for, for instance, inhibiting the influx of inflammatory cells to tissues as well as for increasing the homing of haematopoietic stem cells to the bone marrow after transplantation. We focus on two topics:

The role of negative migratory cues in haematopoietic (stem) cell migration

It was recently shown that the chemorepellent Slit and its receptor Roundabout (Robo) inhibit SDF1/CXCL-12-induced chemotaxis. We therefore study the mechanisms and relevance of Slit-Robo interactions in the control of migration of haematopoietic (stem) cells.

 

The figure depicts a model for the homing and mobilization of hematopoietic stem cells to and from the bone marrow. SDF-1mediated chemotaxis of HSC is counteracted by the Slit-mediated repulsion. Slit acts through its receptor Robo. The balance between the SDF-mediated adhesion and Slit-mediated repulsion determines the whether homing of HSC to the bone marrow occurs, or whether HSC are mobilized into the peripheral blood.

Chemokine receptor trafficking

One of the determinants of CXCL12 signaling is the cell surface expression of its receptor CXCR4. This is regulated by ligand-dependent and ligand-independent internalization, recycling and breakdown of the receptor. We want to unravel the signaling mechanisms involved in CXCL12-induced migration with an emphasis on the regulation of ligand-(in)dependent receptor trafficking.