Deanticoagulated Heparins Mediate Goblet Cell Differentiation to Restore Mucosal Barrier for Ulcerative Colitis Therapy

Abstract Mucosal barrier dysfunction is a pathological hallmark of ulcerative colitis (UC), yet current clinical therapeutic strategies remain predominantly limited to anti-inflammatory therapies and/or surgical treatment, lack of reliable treatment for mucosal repairment1,2. Here, through a systematic screen of our established library for deanticoagulated heparins3, we found that the nonanticoagulant low-molecular-weight heparin NALHP with average Mw 6400 Da and its separated representative fine fragment S6 with average Mw 4200 Da with similar structures exhibited marked therapeutic efficacy for dextran sulfate sodium (DSS)-induced UC mice by ameliorating the pathological phenotypes and repairing intestinal damage. NALHP and S6 were found to specifically mediate differentiation of the crypt stem cells into goblet cells in UC mice, and promote restoration of the damaged mucosal barrier. Notably, using human UC patient-derived organoid models, NALHP and S6 were mechanistically demonstrated to reconstruct the cellular composition profiles, and direct differentiation of the colonic stem cells into goblet cells by regulating Wnt and Notch signaling pathways, thereby facilitating the mucus layer repair. Our study is the first to reveal the main mechanism of deanticoagulated heparins for UC therapy through specifically mediating goblet cell differentiation, providing crucial insights for development of novel UC therapeutics by targeting mucosal barrier repair process. Competing Interest Statement The authors have declared no competing interest. Footnotes Section 1 has been updated to clarify the relevant content regarding NALHP safety; the supplementary data graph has been updated; the author's affiliation information has been updated; the supplementary files have also been updated; the title, abstract, and discussion sections have been updated for some of the terms.