Nonanticoagulated Heparin Derivatives Mediate Goblet Cell Differentiation to Restore the Mucosal Barrier for Ulcerative Colitis Therapy
Hu, W.; Liu, Z.; Huang, L.; Zeng, W.; Ren, X.; Ji, Y.; Zhou, Q.; Xu, B.; Zhang, C. Y.; Zhang, C.; Zhang, Z. Q.; Zhang, H.; Yang, Y. S.; Chen, Y.; Jiang, X.; Wang, Y.; Xing, X.-H.
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Impaired mucosal barrier function is a pathological hallmark of ulcerative colitis (UC), yet current clinical therapeutic strategies primarily rely on anti-inflammatory agents or surgery, lacking strategies to repair mucosal damage1,2. Here, through a systematic screen of our established library of deanticoagulated heparins3, we found that the nonanticoagulant low-molecular-weight heparin NALHP (average Mw, 6400 Da; PDI=2.23) and its separated representative fine fragment S6 (average Mw, 4200 Da; PDI=1.1) significantly ameliorated dextran sulfate sodium (DSS)-induced UC in mice by restoring intestinal integrity. Both compounds promoted crypt stem cell differentiation into goblet cells, thereby repairing the colonic mucosal barrier. Notably, in human UC patient-derived organoids, NALHP and S6 enhanced goblet cell differentiation, increased MUC2 secretion, and modulated Wnt and Notch signaling to optimize epithelial composition. Our study is the first to reveal the therapeutic mechanism of deanticoagulated heparin derivatives in UC through the regulation of epithelial mucosal regeneration via the mediation of goblet cell differentiation, providing crucial insights for the development of novel UC therapeutics capable of targeting the mucosal barrier repair process.
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