Spatial compartmentalization of signaling imparts source-specific functions on secreted factors

Efficient regeneration requires multiple cell types acting in coordination. To better understand the intercel-lular networks involved and how they change when regeneration fails, we profile the transcriptome of he-matopoietic, stromal, myogenic, and endothelial cells over 14 days following acute muscle damage. We generate a time-resolved computational model of interactions and identify VEGFA-driven endothelial engagement as a key differentiating feature in models of successful and failed regeneration. In addition, the analysis highlights that the majority of secreted signals, including VEGFA, are simultaneously produced by multiple cell types. To test whether the cellular source of a factor determines its function, we delete VEGFA from two cell types residing in close proximity: stromal and myogenic progenitors. By comparing responses to different types of damage, we find that myogenic and stromal VEGFA have distinct functions in regener-ation. This suggests that spatial compartmentalization of signaling plays a key role in intercellular communi-cation networks.