Frenette started out not with the nervous system but with a sulfated sugar polymer from seaweed. This sugar could mobilize HSPCs, presumably via an effect on adhesion, and the mouse Cgt enzyme made a sulfated glycolipid that looked similar. Mice lacking this Cgt enzyme had impaired HSPC mobilization.
But ideas about adhesion problems fell away as the team realized that the mutant mice had other problems. The mice have severe defects in their sympathetic nervous system because they cannot make major myelin sheath components. Chemical poisoning of the sympathetic nervous system also led to defects in HSPC mobilization in wild-type mice.
The team found that the sympathetic nervous system works cooperatively with the cytokine G-CSF to change the morphology and behavior of osteoblasts. These bone-generating cells normally make the CXCL12 chemokine, which attracts HSPCs to keep them in the bone marrow. But the G-CSF and sympathetic nervous system signals reduced CXCL12 levels so that HSPCs could escape into the bloodstream.
Enforced mobilization is used clinically to harvest HSPCs, but the physiological significance of the mobilization, and the uses to which these mobilized cells are put, are poorly defined. One report suggests that running a marathon gets HSPCs out, perhaps to do repairs. Frenette plans to test conditions such as these, and to determine what cell type the G-CSF is acting upon.