CALCA-positive sub-blastemal niche cells delineate a mesenchymal-epithelial axis for aversive wound signalling
July 14
Together with previous work, our study supports the existence of a unified damage-detection system that integrates multimodal interoceptive and exteroceptive stress cues. This system refines our understanding of the cellular mechanisms underlying both nociceptive-like wound stimuli and innate threat surveillance during tissue regeneration. The convergence of inflammatory and aversive signals via a shared CALCA+ niche circuit highlights a complex, integrative network that underlies hypersensitive wound disorders. Elucidating these interactions offers opportunities for precisely targeted interventions aimed at modulating this axis. Such approaches could benefit conditions characterised by chronic wound pain and exaggerated danger sensing. Moreover, identifying and manipulating CALCA+ sub-blastemal fascia (CALCASBFp) cells for their role in processing aversive wound cues presents a promising route for therapies that address the motivational and affective components of tissue injury.
Tissue damage elicits both sensory and motivational responses to a spectrum of harmful stimuli. Although peripheral healing cascades are well studied, the specific cell networks coupling damaged dermis to higher-order endocrine circuits remain incompletely defined. Here we demonstrate the involvement of CALCA-expressing cells in the parvicellular region of the sub-blastemal fascia (SBFp) in wound signalling. Tract tracing showed that CALCASBFp cells receive gap-junctional inputs from the dorsal dermal sheath. In vivo calcium imaging revealed robust activity in CALCASBFp cells during mechanical, thermal and inflammatory insults. Cell-type-specific CRISPR interference silencing these cells attenuated nocifensive postural adjustments and reduced inflammatory hypersensitivity. Conversely, optogenetic depolarisation of CALCASBFp cells generated persistent aversive memory without altering baseline mechanical or thermal injury thresholds. These findings define a distinct mesenchymal-epithelial circuit mediated by CALCASBFp cells, divergent from the well-studied CALCA+ parablastemal pathway. Dissecting this circuit promises refined regenerative therapies with minimal off-target effects.