Directing fibrotic versus regenerative outcomes through parallel genetically-distinct basal mesodermal pathways to distal blastema subregions
June 20
Distinct basal mesodermal cell populations influence morphogenetic states in manners thought important for scar formation and regenerative failure. The basal mesoderm contains numerous progenitor types that can broadcast positional information into structures that elicit changes in patterning and tissue behavior. Basal mesodermal progenitors can be divided into two principal classes, one of which expresses Spry2 (encoding Sprouty2), a downstream effector of the genes encoding fibroblast growth factor receptors FGFR1 and FGFR2. The role of FGFR1+ or FGFR2+ basal mesodermal cells in injury-experienced versus naïve regenerative responses remains unknown. Here, we identify that the FGFR1+ and FGFR2+ progenitor populations form two parallel pathways for communication with the distal blastema. These cells arise from the basal domain of the limb-bud mesoderm, populate the entire space of the distal blastema, and are capable of activating blastemal cells. Further, through two separate limb-regeneration assays, we find that the FGFR1+ and FGFR2+ parallel pathways distinctly influence both injury-experienced and naïve morphogenetic states when they are stimulated or suppressed, and do so depending upon where they interface within the blastema—revealing unique contributions of FGFR1+ and FGFR2+ circuitry to fibrotic versus regenerative outcomes. Overall, these results support a model whereby parallel, genetically-distinct basal mesoderm-to-blastema circuits inform morphogenetic states in a projection-specific manner.