SUN-552 Evidence for Endocrine Cell Regeneration in the Human Pancreas: Regions of Exocrine Metaplasia Contain More Endocrine Cell Clusters Than Normal Exocrine Regions

Abstract Disclosure: N. Trumble: None. A. Eskaros: None. A.L. Hopkirk: None. P. Jackson: None. J.J. Wright: None. The exocrine and endocrine compartments of the pancreas are functionally distinct but share close spatial and embryologic relationships. In type 1 diabetes (T1D), insulin-producing beta cells are destroyed, so identifying sources of replacement beta cells is an important step toward improved treatment of the disease. While some conditions, like obesity and pregnancy, induce the expansion of functional endocrine cell mass, the source of increased beta cell mass in the human pancreas remains unknown. Acinar-to-ductal metaplasia (ADM) represents an adaptive reaction in the exocrine pancreas in response to an environmental injury. We recently reported that ADM is increased with age and in type 2 diabetes (T2D), but not in T1D. We hypothesize that cellular reprogramming in regenerating exocrine tissue within areas of ADM also results in the proliferation of endocrine cells. Transplant-grade human pancreas tissue from donors with no diabetes (ND, n = 35), T1D (n = 12), and T2D (n = 24) were studied by the Human Pancreas Analysis Program (https://hpap.pmacs.upenn.edu). Tissue sections were stained with antibodies for C-peptide (CPEP), glucagon (GCG), and somatostatin (SST) using the CODEX multiplex imaging system (Akoya Biosciences) followed by H&E to identify regions of normal acinar tissue, normal ducts, and ADM. Endocrine cells were quantified in these regions based on CODEX staining, excluding large islets (>2,000µm2) from the analysis. HPAP donor information and CODEX images are available at PANC-DB (https://hpap.pmacs.upenn.edu) and https://www.pancreatlas.org. Among all donors, regions of normal duct were found to have a higher percentage of GCG, CPEP, and SST-positive cells than normal acinar tissue (GCG 0.36 ± 0.08 vs 0.15 ± 0.03%, p < 0.05; CPEP 0.50 ± 0.09 vs 0.27 ± 0.04%, p = 0.053; SST 0.25 ± 0.04 vs 0.065 ± 0.01%, p < 0.0001; n = 69). ADM regions had more hormone-positive cells than typical acinar regions (GCG 1.68 ± 0.5 vs. 0.11 ± 0.04%, p < 0.01; CPEP 2.87 ± 1.08 vs. 0.27 ± 0.05%, p < 0.05; SST 0.51 ± 0.20 vs. 0.068 ± 0.04%, p < 0.05; n = 16) and more GCG and CPEP than typical ductal regions (GCG 1.68 ± 0.49 vs 0.44 ± 0.13%, p < 0.05; CPEP 2.87 ± 1.08 vs 0.77 ± 0.30%, p = 0.065; n =16). Comparing endocrine cell percentages in these regions between ND and T1D donors, we found a greater percentage of GCG and SST-positive individual cells in T1D donor acinar tissue compared to ND donors (GCG 0.36 ± 0.12 vs 0.11 ± 0.037%, p < 0.05; SST 0.18 ± 0.05 vs 0.095 ± 0.03%, p < 0.0001; n =12 T1D and 27 ND) and no difference in the ADM regions between T1D and ND donors. The combination of traditional histologic and advanced multiplex immunostaining shows that regions of ADM have a greater percentage of small endocrine cell clusters than normal acinar or ductal tissue. These small cell clusters may represent regenerating endocrine cells, though further work is needed to understand their source and the dynamic processes that cause these changes. Presentation: Sunday, July 13, 2025