Hyaluronic Acid and Emergent Tissue Mechanics Orchestrate Digit Tip Regeneration

Tissue regeneration is a dynamic process requiring coordinated cell fate decisions to restore structure and function. For instance, the tips of human and rodent digits fully regrow after amputation, although more proximal injuries fail to regenerate. While biochemical cues have been widely studied in wound healing, the role of the physical microenvironment remains less understood. Here, we discovered that tissue mechanics and extracellular matrix (ECM) composition differ markedly between non-regenerating and regenerating wounds. These differences are due to specific fibroblast sub-types which predominate in the non-regenerating wound and form fibrotic collagen networks. Conversely, bone-forming progenitors in regenerating digits synthesize abundant hyaluronic acid, which mediates collagen fibrillogenesis. By modeling the tissue mechanics of non-regenerative and regenerative wounds using hydrogels, we showed that substrate stiffness regulates the synthesis of fibrotic and regenerative ECM. We further revealed that mimicking the regenerative wound mechanics upregulated bone morphogenic protein signaling and osteogenic differentiation. We ultimately demonstrated that the link protein HAPLN1 promotes hyaluronic acid deposition in vivo, reduces scar formation, and induces bone repair after non-regenerative amputations. These findings emphasize the interplay among the ECM, tissue mechanics, and cell behavior in digit regeneration and point towards ECM modulation as a strategy to improve wound healing. HighlightsO_LINon-regenerating and regenerating digit tips diverge in their cellular and ECM composition C_LIO_LIRegeneration requires hyaluronic acid matrix, which mediates collagen assembly and tissue mechanics C_LIO_LISoft substrates enhance BMP signaling and propagate the synthesis of regenerative ECM C_LIO_LIHAPLN1 overexpression initiates rescue of non-regenerative digit tip amputations C_LI