《Science》: Hyaluronic Acid and Tissue Mechanics Synergistically Regulate Mammalian Digit Tip Regeneration
Release time:
2026-06-26
Recently, the international top academic journal Science published online a significant research finding from the team led by Mekayla A. Storer at the University of Cambridge. This study reveals that the composition and mechanical properties of the extracellular matrix (ECM) serve as a critical "switch" determining whether mammalian tissues undergo regeneration or fibrotic scar repair, offering a fresh perspective for regenerative medicine.
Regeneration vs. Scarring: Two Distinct Microenvironments
In mammals (including humans), injuries typically culminate in scar healing, but the digit tip is a rare exception—amputation at the distal phalanx (P3 region) enables complete multi-tissue regeneration, whereas the proximal phalanx (P2 region), closer to the torso, only forms scar tissue.
Using a mouse digit tip amputation model, the research team found that the root of this difference lies in the extracellular matrix microenvironment at the injury site. The non-regenerative region exhibits stiff tissue with a dense, organized collagen network, whereas the regenerative region is softer, more fluid, and rich in hyaluronic acid (HA). Atomic force microscopy measurements confirmed that non-regenerative wounds are significantly stiffer than regenerative blastema tissues.
Hyaluronic Acid: The Core Driver of Regeneration
The study found that hyaluronic acid is not merely a passive matrix component but actively inhibits collagen assembly, preventing fibrosis. When the researchers depleted hyaluronic acid using hyaluronidase or the drug 4-methylumbelliferone (4-MU), the otherwise regenerative distal amputations shifted toward fibrosis—blastema formation was blocked, osteoblasts decreased, and bone repair failed. This series of experiments confirmed that hyaluronic acid is a necessary driver of digit tip regeneration.
HAPLN1: The Key Protein That Rewrites Fate
The team further pinpointed hyaluronic acid and proteoglycan link protein 1 (HAPLN1). HAPLN1 stabilizes the hyaluronic acid network and maintains the soft mechanical properties of the tissue. By overexpressing HAPLN1 in a non-regenerative amputation model, the researchers successfully induced bone tissue regeneration where it had previously been impossible—bone growth extended beyond the original amputation plane, scar-like collagen structures were markedly reduced, and tissue stiffness decreased while fluidity increased.
At the mechanistic level, the study confirmed that a soft matrix environment enhances cellular responsiveness to bone morphogenetic protein (BMP) signaling—fibroblasts cultured on soft matrices exhibited significantly higher pSMAD1/5/8 signaling levels than those on stiff matrices. This explains how the mechanical microenvironment directly regulates cellular regenerative behavior.
From Targeting Cells to Engineering the ECM
This study is the first to systematically elucidate the core mechanism by which ECM composition and mechanical properties act as a "switch" between regeneration and fibrosis in mammals. The team proposes that the perspective of regenerative medicine should shift from "targeting cells" to "engineering the extracellular matrix"—by modulating the physical microenvironment rather than merely intervening in cells, it may be possible to unlock the intrinsic regenerative potential of mammals. This discovery opens entirely new research avenues for anti-fibrotic therapies and tissue repair.
This work was completed by scholars including Mui, Wong, and Storer from the University of Cambridge. In the same issue, Science also published a related study on oxygen-sensing regulation of limb regeneration, collectively providing important breakthroughs in understanding the mechanisms of mammalian regeneration.
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