Hyaluronic acid and tissue mechanics orchestrate mammalian digit tip regeneration

• 成果类型: Article
• 署名作者: Mui, Byron W. H.; Wong, Joseph J. Y.; Dumas, Camille E.; Wang, Jia Hua; Bray, Toni; Hirose, Kentaro; Connolly, Lauren; Winkel, Alexander; Timmler, Sebastian; Bright, Nicholas A.; Sliauteryte, Evelina; Karadottir, Ragnhildur Thora; Robey, Pamela G.; Franze, Kristian; Chalut, Kevin J.; Storer, Mekayla A.
• 署名单位: University of Cambridge; National Institutes of Health (NIH) - USA; NIH National Institute of Dental & Craniofacial Research (NIDCR); National Institutes of Health (NIH) - USA; Stanford Medicine; Stanford University; University of Cambridge; University of Cambridge; University of Iceland; University of Erlangen Nuremberg; UK Research & Innovation (UKRI); Biotechnology and Biological Sciences Research Council (BBSRC); Babraham Institute
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.ady3136
• 发表日期: 2026-04-09
• 页码: eady3136
• 关键词: DERMAL FIBROBLASTS; LINK-PROTEIN; matrix; injury; degradation; fibronectin; requirement; homeostasis; responses; fibrosis

摘要

Tissue regeneration is rare in mammals, but the digit tip can regrow after amputation, whereas injuries beyond the nail do not. How the microenvironment drives divergent outcomes remains unclear. In this study, we found that the extracellular matrix (ECM) and tissue mechanics govern the amputation response in mouse digits. Nonregenerative regions were stiffer and contained dense, organized collagen, whereas regenerative regions were soft and enriched in hyaluronic acid (HA). Depleting HA inhibited regeneration and promoted fibrosis, demonstrating that the HA-collagen balance shaped tissue mechanics and repair signaling. Stabilization of HA with hyaluronan and proteoglycan link protein 1 (HAPLN1) after nonregenerative amputations tuned ECM mechanics, reduced scarring, and enhanced bone repair. Thus, ECM composition and mechanics influence cell behavior and ECM-targeted strategies could help unlock mammalian regeneration.