2675-P: Deletion of SMOC1 Impairs Endocrine Cell Fate Acquisition in Human Stem-Cell–Derived Pancreatic Islets

Introduction and Objective: Loss of β-cell identity and dedifferentiation toward an α cell-like state are hallmarks of type 2 diabetes (T2D). SMOC1 (Secreted Modular Calcium-binding protein 1) misexpression in T2D human islets associates with a reduction of insulin expression and β cell dysfunction. SMOC1, found in basement membranes, influences growth factor action and affects cell differentiation, with key roles in ocular and limb development. However, whether SMOC1 has a physiological role during human endocrine cell development and maturation is unknown. Methods: Differentiation of human pluripotent stem cells (H1, WiCell) into islets (SC-islets, Hogrebe et al 2021) was used to investigate the role of SMOC1 during human β cell development. SMOC1 knockout (KO) and inducible knock-in (KI) SC-islet lines were generated using CRISPR/Cas9-mediated genome editing. Endocrine cell identity, numbers, and maturation were assessed by immunostaining and functional analyses. Results: SMOC1 expression was dynamically regulated during SC-islet differentiation, suggesting a potential role distinct from its pathological association in adult T2D islets. SMOC1 KO SC-islets exhibited a pronounced selective reduction of NKX6.1 expression while maintaining normal PDX1 and NGN3 expression, consistent with impaired endocrine cell fate stabilization rather than defective lineage specification. Although overall SC-islet size and gross morphology were comparable between control and SMOC1 KO cells, the proportion of NKX6.1+ β cells was markedly reduced. In contrast, SMOC1 KI expression preserved NKX6.1+ β cell identity and supported functional maturation. Conclusion: These findings identify SMOC1 as a regulator of human β cell development and identity, functioning as a physiological stabilizer of SC-islets. SC-islets provide a powerful human platform to define stage-specific regulators of β cell identity with relevance to diabetes pathogenesis and replacement therapies. Disclosure J. Park: None. J. Lee: None. J. Aldaco: None. M. Varela: None. R.B. Kang: None. G. Lu: None. A. Garcia-Ocana: Advisory Panel; Current; Paulex Bio.