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

Abstract

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. We synthesised sulphated hyaluronic acid (sHA) with an affinity for the latent complex of transforming growth factor-β (TGF-β) 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-β. 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. 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. 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. Cell transplantation may provide a lifeline to millions of patients with end-stage liver diseases, but their severely damaged livers being unable to accommodate the transplanted cells is a crucial hurdle. Herein, we report an approach to restore liver functions in another organ - the spleen - by activating one single growth factor in situ. This approach, based on a chemically designed polysaccharide that can mechanically liberate the active transforming growth factor-β to an unusually high level, promotes the function of abundant allogenic liver cells in the spleen, rescuing animals from lethal models of liver diseases and showing a high potential for clinical translation.