Salamanders possess the ability to regenerate their entire limbs. Such regenerative capacity requires the formation of the blastema, a transient cellular structure comprised of progenitors that are derived from several different tissues. In this article, Douglas Melton and colleagues exploit the regenerative capacity of the axolotl to identify the early transcriptional programmes that are active in blastema formation. The authors produce transcriptional profiles of blastemal progenitors by selectively isolating distinct populations of proliferating cells from the limb stump during early regeneration. They reveal that transcripts involved in extracellular matrix remodelling and TGF-β signalling are specifically upregulated in dividing cells. Surprisingly, some core signalling pathways that are required for complete limb regeneration, such as FGF, are initially supressed in blastemal progenitors. In addition, the data show enrichment of the chemokine interleukin-8 (IL-8) in dividing blastemal progenitors. Knockdown of IL-8 or inhibition of the cognate receptor CXCR-1/2 impairs limb regeneration, whereas ectopic expression of il-8 in the limbs recruits myeloid cells. These results suggest that the early blastema regulates the immune system through chemokine signalling – and that this signalling is important for regeneration. Building on previous work that shows the immune system regulates blastema development, this study demonstrates bidirectional signalling between the blastema and the immune system.
