Molecular force-induced liberation of transforming growth factor-beta remodels the spleen for ectopic liver regeneration

Abstract

Background & Aims

Ectopic liver regeneration in the spleen is a promising alternative to organ transplantation for treating liver failure. To accommodate transplanted liver cells, the splenic tissue must undergo structural changes to increase extracellular matrix (ECM) content, demanding a safe, efficient approach for tissue remodelling.

Methods

We synthesised sulphated hyaluronic acid (sHA) with an affinity for the latent complex of TGF-β and cross-linked it into a gel network (sHA-X) via click chemistry. We injected this glycan to remodel the splenic tissue by activating endogenous transforming growth factor-beta (TGF-β) to a supraphysiological level.

Results

sHA-X efficiently bound to the abundant latent TGF-β in the spleen. It provided the molecular force to liberate the active TGF-β dimers from their latent complex, mimicking the ‘bind-and-pull' mechanism required for physiological activation of TGF-β and reshaping the splenic tissue to support liver cell growth. Strikingly, hepatocytes transplanted to the remodelled spleen developed into the liver tissue with sufficient volume to exert potent functions for rescuing the animals with 90% hepatectomy and metabolic liver disorder (in Fah^-/- transgenic model), with no adverse effects observed and no additional drugs required.

Conclusion

; Our findings highlight the efficacy and translational potential of sHA-X to remodel a specific organ by mechanically activating one single cytokine, representing a novel strategy for designing biomaterials-based therapies for organ regeneration.