Low-dose irradiation enhances limb regeneration (bottom) unless mast cells are absent (top).

Irradiation instructs mast cells to rebuild blood vessels in oxygen-deprived tissues, according to Heissig and colleagues on page 739. Low-dose irradiation mobilized adult and precursor mast cells, which traveled to the ischemic tissue and produced the vessel-building growth factor VEGF (vascular endothelial growth factor).

Ionizing irradiation has been shown to promote the growth of new blood vessels through the induction of VEGF and inhibition of endothelial cell death. However, the primary source of irradiation-induced VEGF and the precise mechanism that triggers its production were not clear. Mast cells—well-known for their production of histamine in allergic responses—had been found in tissues undergoing angiogenesis. Mast cells are also capable of producing VEGF, but whether these cells play a leading or supporting role in angiogenesis had not been explored.Heissig et al. now show that mast cells are essential for irradiation-induced vessel growth in a mouse model of ischemic limb injury. Irradiation-induced cellular damage triggers the production of the degradative enzyme matrix metalloprotease-9 (MMP-9) by largely unknown mechanisms. In this model, local irradiation of the damaged limb increased MMP-9 production in the ischemic tissue, which liberated the cytokine Kit ligand (KitL), likely from stromal cells. KitL then attracted VEGF-producing mast cells into the injured tissue.

At the same time, irradiation mobilized mast cell precursors and endothelial cell progenitors from the bone marrow, and some of these cells became incorporated into the growing vessels. Without mast cells, the vessel-building benefits of irradiation were lost. The authors thus speculate that localized irradiation might improve upon current therapies for organ regeneration, which rely on the injection of large numbers of bone marrow–derived stem cells directly into damaged organs.