Molecular force-induced supraphysiological liberation of transforming growth factor-beta (TGF-β) remodels the spleen for liver tissue growth

Although the spleen is one potential transplantation site in liver regeneration, its native microenvironment is adverse for the stabilisation of epithelial hepatocytes after transplantation, due to the scanty collagen therein could not provide sufficient adhesion anchorage sites. Based on the crucial role of TGF-β in increasing collagen, its unique physiological status in the spleen, and its special mechanical force-mediated activation, we speculated the active TGF-β could be exploited from the storehouse of LLC in spleen by mimicking the procedure of TGF-β release. Thus, we designed a bifunctional sHA-X biomaterial integrating with the capacity of binding with LTBP1 and providing mechanical force. The network effectively enhanced the release of TGF-β from LLC, remodelled the spleen microenvironment in situ by increasing collagen abundance, promoted the adhesion and growth of hepatocytes, and then achieved the hepatisation of the spleen. The hepatised spleen could display liver-like function and survive in the liver metabolic diseases model and after liver resection. Our study confirmed the feasibility and advantages of in situ regulating TGF-β bioavailability in remodelling spleen niches and liver regeneration. Our study, for the first time, demonstrates an engineered approach to harness endogenous TGF-β functions for ectopic tissue regeneration, through mechanical manipulation of its unique mechanism of activation.