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

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 content, demanding a safe and efficient approach for tissue remodelling. Methods: We synthesised sulphated hyaluronic acid (sHA) with an affinity for the latent complex of transforming growth factor -8 (TGF-8) and cross -linked it into a gel network (sHA-X) via click chemistry. We injected this glycan into the spleens of mice to induce splenic tissue remodelling via supraphysiological activation of endogenous TGF-8. Results: sHA-X efficiently bound to the abundant latent TGF-8 in the spleen. It provided the molecular force to liberate the active TGF-8 dimers from their latent complex, mimicking the 'bind -and -pull' mechanism required for physiological activation of TGF-8 and reshaping the splenic tissue to support liver cell growth. Hepatocytes transplanted into the remodelled spleen developed into liver tissue with sufficient volume to rescue animals with a metabolic liver disorder ( Fah -/- transgenic model) or following 90% hepatectomy, with no adverse effects observed and no additional drugs required. Conclusion: Our findings highlight the efficacy and translational potential of using sHA-X to remodel a specific organ by mechanically activating one single cytokine, representing a novel strategy for the design of biomaterials-based therapies for organ regeneration. (c) 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.