02838nas a2200325   4500000000100000000000100001008004100002260001500043100002100058700002000079700001800099700002100117700002200138700002000160700001600180700002200196700001400218700002000232700001800252700001900270700002000289700001800309700001700327700001900344700002400363700002100387245013600408856006400544520190400608       2025                            d  c2025-05-071 aAnna Stejskalova1 aKarina Calderon1 aDavid B. Chou1 aAakanksha Gulati1 aJessica F. Feitor1 aZohreh Izadifar1 aOla Gutzeit1 aYasmine Bouchibti1 aSiyu Chen1 aRoberto Plebani1 aJustin Cotton1 aJasmine Hughes1 aThomas Ferrante1 aBogdan Budnik1 aGirija Goyal1 aAbidemi Junaid1 aCarlito B. Lebrilla1 aDonald E. Ingber00aInduction of cervical dysfunction associated with preterm birth by IL-1 and dysbiotic microbiome revealed in human endocervix chips  uhttps://www.biorxiv.org/content/10.1101/2025.05.01.651107v13 aCervical dysfunction, a major contributor to preterm labor and neonatal mortality, remains poorly understood due to the absence of physiologically relevant human models. Here, we show that a microfluidic human Endocervix Chip lined by primary endocervical epithelium interfaced with stromal cells and cultured under pregnancy-like hormonal conditions recapitulates key aspects of the biology of the endocervix, including formation of a mucus plug-like structure with antimicrobial properties. Culturing a dysbiotic cervico-vaginal microbiome on-chip increased secretion of pro-inflammatory cytokines observed in patients with preterm labor and enhanced production of matrix metalloproteinases (MMPs) that degrade stromal extracellular matrix (ECM). Perfusion with inflammatory cytokines at clinically relevant concentrations altered cervical mucus composition, upregulated prostaglandin-endoperoxide synthase 2 expression, increased MMP secretion, and reduced collagen production, which together drive dissolution of the stromal ECM and promote cervical ripening. Addition of circulating peripheral blood mononuclear cells (PBMCs) amplified these effects. Administration of a clinically approved drug for prevention of preterm labor that the Food and Drug Administration (FDA) recently deemed ineffective was also found to be inactive in the chip, while an approved therapeutic antagonist of the IL-1 receptor successfully protected against cervical dysfunction in this model. These findings demonstrate that IL-1 acts directly on human cervical tissues to promote changes associated with initiation of labor and that primary human endocervix chips may represent a useful preclinical model for studies on cervical dysfunction associated with preterm birth.
One Sentence Summary Human endocervix chip modeling of cervical dysfunction suggests that IL-1 receptor antagonists may prevent preterm labor.