Tuning regenerative activation
June 19
The blastema organiser (BO), a principal source of pro-growth FGF8 during appendage regrowth, is central to coordinating regenerative activation and patterning. Yet the mechanisms that restrain BO activity—particularly the influence of neighbouring inhibitory mesenchymal cells—remain obscure. Here we identify a heterogeneous peri-BOBMP high population that directly attenuates BO signalling, thereby modulating outgrowth and fibrosis during mouse digit-tip regeneration.
Using optogenetic activation of a light-gated BMP receptor and chemogenetic silencing via a ligand-gated chloride channel, we show that stimulating peri-BOBMP high cells markedly suppresses proliferation and epithelial migration, whereas transient suppression of these cells enhances blastema expansion but provokes anxiety-like wound behaviour, manifested as excessive collagen deposition and avoidance of re-epithelialisation fronts.
Single-nucleus RNA-seq and spatial transcriptomics in actively regenerating digits revealed unexpected molecular diversity within both peri-BO and BO compartments. Distinct secreted-peptide-expressing subclusters—defined by Tac1, Penk or Cartpt—displayed stimulus-specific calcium dynamics in vivo and differentially regulated either mitotic index or matrix remodelling when selectively photo-stimulated.
Collectively, these findings position peri-BOBMP high cells as critical regulators of BO output, linking their activity to regenerative amplitude and scar formation. Targeting defined peri-organiser subtypes may provide therapeutic entry points for enhancing human tissue repair while limiting fibrosis.
Translated from Tuning arousal