Diabetes Enhances the Proliferation of Adult Pancreatic Multipotent Progenitor Cells and Biases Their Differentiation to More β-Cell Production

Abstract

Endogenous pancreatic multipotent progenitors (PMPs) are ideal candidates for regenerative approaches to compensate for b-cell loss since their b-cell-producing capacities as well as strategic location would eliminate unnecessary invasive manipulations. However, little is known about the status and potentials of PMPs under diabetic conditions. Here we show that b-cell metabolic stress and hyperglycemia enhance the proliferation capacities of adult PMP cells and bias their production of progeny toward b-cells in mouse and human. These effects are dynamic and correlate with functional b-cell regeneration when conditions allow.

Virgin Beta Cells Persist throughout Life at a Neogenic Niche within Pancreatic Islets

“…These and similar cells found in small clusters outside of normal islets (Beamish et al, 2016) share a lack of cell-surface Glut2 with the immature beta cells we discovered at the niche. However, the genes enriched in the PMP transcriptome (Razavi et al, 2015) demonstrate virtually no overlap with those enriched in immature beta cells ( Figure S4). Moreover, while we consider Ucn3-negative immature beta cells to be a reservoir of beta cell progenitors, we do not have evidence to suggest that they possess the multipotent progenitor properties described for PMPs.…”

“…All Venn diagrams were generated using the R library package VennDiagram (Chen and Boutros, 2011), using the edgeR output and our FDR and log2FC filtering criteria for gene selection. We included a lower RPKM threshold of 1 when comparing our immature beta cell transcriptomes with those of the PMPs (Razavi et al, 2015). KEGG gene set enrichment testing was performed on the immature beta data set using the R Bioconductor package GAGE (Luo et al, 2009) on the edgeR output that met the statistical threshold.…”

“…Related to Figure (A-H) Immunofluorescence image and distribution of alpha, mature beta, Ucn3 low beta, and Ucn3-negative immature beta cells (arrows) across the islet at these ages: (A) P2 (B) P7 (C) 3 weeks (D) 6 weeks (E) 9 weeks (F) 3 months (G) 8 months (H) 14 months Table S1 lists the P value and D statistic for each pairwise comparison at each age. (Razavi et al, 2015). (B) Heat map analysis of genes most differentially expressed in human beta cell subtypes based on expression of ST8SIA1.…”

“…Heat maps were generated based on the n most up-and n most down-regulated genes between each pairwise comparison, with duplicate genes removed, where n = 750 for Figure 2G and n = 200 for Figure 6K. To enable the most direct comparison, the same analysis pipelinefrom raw sequencing reads, to quantification and differential analyses-was also 38 applied to compare our data against mouse PMPs (Razavi et al, 2015) and human beta cell subtypes (Dorrell et al, 2016). Distance matrices for the latter comparison were generated using the R package lattice, with RPKM values from each experiment used to correlate relatedness.…”

La thérapie cellulaire du diabète

“…Ces progéni-teurs pancréatiques (baptisés PMP pour pancreatic multipotent progenitors) expriment l'insuline mais pas le transporteur de glucose GLUT2. Cette caracté-ristique permet de les sélec-tionner au sein d'îlots par un traitement à la streptozotocine qui enrichit les cultures en populations de cellules insuline + /GLUT2 faible [35]. En culture, les PMP ont des facultés spontanées de différenciation en cellules β fonctionnelles et en lignées neuronales.…”