Targeting Fibrotic Scarring by Mechanoregulation of Il11ra1

Fibrotic scarring remains a critic obstacle to axonal regeneration after spinal cord injury (SCI). Current strategies primarily concentrating on eliminating extracellular matrix (ECM) components neglect their dispensable roles in maintaining tissue integrity. Here, it is reported that the mechanical strength of an integrated hydrogel composed of hyaluronic acid-graft-dopamine and HRR peptide directs fibroblast migration, determining ECM deposition. The mechanical strength matching that of spinal cord induces fibroblast alignment, reshaping fibrotic scars into a parallel matrix, while the mechanical strength deviating from that of spinal cord fails to do so. Mechanical investigation identifies a previously unknown Il11ra1+/Itga11+ fibroblast subset that is specially associated with aligned infiltration and parallel ECM via mechanotransduction signaling cascade LRP6/β-Catenin/MMP7, promoting axonal regeneration and boosting neural reconnections across the lesion. The study uncovers the mechanotransduction mechanism that remodels fibrosis progression through manipulating cellular components of fibrotic scars, providing novel insights into discovering potential therapeutic targets to resolve fibrosis after SCI.