The different cellular compartments of the pancreas have a high degree of plasticity, which, if harnessed, could have important therapeutic implications for beta-cell regeneration in type 1 and type 2 diabetes. This proposal focuses on high-resolution characterization of ductal progenitor-like cells (P2RY1+/ALK3+) and exocrine-endocrine communication in live human pancreatic slices. We will use dynamic single-cell RNA sequencing, live imaging/lineage tracing, spatial transcriptomics, and pharmacological perturbation with BMP pathway agonists and other candidate regenerative agents to define ductal remodeling, beta-cell neogenesis, and tissue-level signaling in human pancreatic tissue. This revised application clarifies that rare T1D and AAb+ slices will be used only for experiments requiring the diabetic or prediabetic tissue context, after technical optimization in non-diabetic control slices whenever possible.
