*Purpose: We have previously described a novel population of cells developed from human islets called AIPCs (Activated Islet Proliferating Cells). AIPCs co-express CD133, glucagon and insulin, secrete both hormones when stimulated with various secretagogues, and spontaneously form de novo-pseudo islets. Human AIPCs secrete human insulin when injected in mice for the duration of the observation (more than 90 days). AIPCs represent not only a novel cell population and a tool to foster studies of islet cell biology, but a realistic cellular approach for the treatment of insulin insufficiency in diseases such as diabetes and pancreatitis.

*Methods: In the current study we aimed at further characterizing AIPCs by RNA sequencing pancreatic tissue, AIPCs and denovo-pseudo-islets from the same deceased donor, using Illumina® NovaSeq™ platform.

*Results: AIPCs generated from pancreatic tissue exhibited a substantial decrease in markers of exocrine function (AMY and CTRC), which are expressed in the native pancreas. Concurrently, markers of proliferation PCNA and CCND1 (cyclin family) increased in expression in the AIPCs, potentially signifying dedifferentiation to motile, proliferating cells, consistent with the observation of cell expansion in vitro. Following longer periods of culture (~20 days or more), the AIPCs underwent morphological re-arrangement and spontaneously generated pseudo-islets. These islet-like structures were characterized by a significant increase in expression of a endocrine progenitor and islet signatures that included INS, GCG, PDX-1, SST, IIAP, Pax4, Pax-6, NKx2, Nkx6, NeuroD1, MafA, and MafB, while exhibiting downregulation of the cell proliferation pathways. Moreover, IGFBP1, a marker of β−cell regeneration, was found expressed at higher levels in pseudo-islets when compared to AIPCs, whereas the stem cell markers LY6E and PROM1 were more highly expressed in AIPCs, suggesting the maturation to a more differentiated endocrine progenitor cell population committed to generate alpha, beta and delta cells.

*Conclusions: Altogether, this data suggests that AIPCs derived from pancreatic tissue represent an endocrine progenitor cell population that can spontaneously evolve and mature into pseudo-islets. The islet-like structures exhibit a defined gene expression profile consistent with the differentiation of islet cell subpopulations alpha, beta, delta and PP. This data, coupled with our previous work, reemphasizes the potential of AIPCs as a source of endocrine tissue with therapeutic importance for the treatment of diabetes as well as other insulin insufficiencies.

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