CD168 Identifies Proliferating Pancreatic Islet Cells in Murine and Human

Restoring functional β-cell mass through proliferation is a central goal of diabetes therapy, but progress has been hampered by the inability to isolate live, proliferating β-cells for study. Here, CD168 is identified as a conserved surface marker that specifically enriches for proliferating cells in mouse and human pancreatic islets. Single-cell RNA sequencing reveals a distinct cluster of islet cells with high proliferative activity, low insulin expression, and specific CD168 expression. Flow cytometry and immunostaining confirm CD168⁺ cells co-localize with Ki67⁺ proliferating cells, reside in G2/M phase, and comprise ≈0.5% of adult islet cells. Using a new CD168-CreERT2 mouse model for lineage tracing, it is demonstrated that CD168⁺ cells rapidly divide, forming two-cell clones within hours. Unbiased lineage tracing shows 87.4% of clones are uni-β lineage, with smaller proportions of uni-α, uni-δ, and multi-lineage. Integrated lineage tracing with multi-omics maps a ≈60-day maturation trajectory for nascent β-cells, involving progressive epigenome remodeling and shifting transcriptional networks. Notably, CD168 expression is conserved in proliferating cells of human islets and pancreatic neuroendocrine tumors, highlighting its clinical relevance. This work establishes CD168 as a marker for proliferating islet cells, providing a tool to study β-cell proliferation and novel insights into islet cell proliferation and maturation mechanisms.