Progenitor cell domains in the developing and adult pancreas

Abstract

Unlike organs with defined stem cell compartments, such as the intestine, the pancreas has limited capacity to regenerate. The question of whether the adult pancreas harbors facultative stem/progenitor cells has been a prime subject of debate. Cumulative evidence from recent genetic lineage tracing studies, in which specific cell populations were marked and traced in adult mice, suggests that endocrine and acinar cells are no longer generated from progenitors in the adult pancreas. These studies further indicate that adult pancreatic ductal cells are not a source for endocrine cells following pancreatic injury, as previously suggested. Our own studies have shown that adult ductal cells reinitiate expression of some endocrine progenitor markers, including Ngn3, after injury by partial duct ligation (PDL), but that these cells do not undergo endocrine cell differentiation. Here, we present additional evidence that endocrine cells do not arise from ducts following b-cell ablation by streptozotocin or by a diphtheria toxin-expressing transgene or when b-cell ablation is combined with PDL. In this review, we discuss findings from recent lineage tracing studies of embryonic and adult pancreatic ductal cells. Based upon the combined evidence from these studies, we propose that multipotency is associated with a specific transcriptional signature

G rowth factors and medium hyperglycemia induce Sox9 + ductal cell differentiation into β cells in mice with reversal of diabetes

“…This result may be due to the fact that the maturation of β cells derived from Sox9 + ductal cells is slower than replication of mature β cells, as indicated by previous publications (13). This observation may provide an explanation for previous publications showing that Sox9 + ductal cells and other pancreatic ductal cells did not differentiate into β cells in Alloxaninduced diabetic mice after 1 wk of treatment with GE (14); this finding also provides an explanation for the lack of Sox9 + ductalderived β cells in STZ-induced diabetic mice with high hyperglycemia (∼500 mg/dL) and in the absence of administration of growth factors (16,18). Therefore, we agree with a recent review by Lysy et al that neogenesis from ducts is influenced by the type and extent of pancreatic injury as well as dependent on the affected cell types (30,31).…”

“…Breeders of Sox9 CreERT2 mice were described (17,18) and provided by M. Sander's laboratory at the University of California, San Diego. ROSA26 mT/mG breeders were provided by the C.-C.C.…”

“…Conversely, using a lineage-tracing model with a hepatocyte nuclear factor 1-β (Hnf1β) promoter, Solar et al found that pancreatic ductal cells did not give rise to β cells in neonates, PDL-treated adult mice, or Alloxan-induced diabetic adult mice treated for 1 wk with GE (14). Using a lineage-tracing model with a SRY (sex-determining region Y)-box 9 (Sox9) promoter, Kopp et al also showed that Sox9 + ductal cells did not give rise to β cells postnatally after β-cell ablation or after PDL (17,18). Similarly, Furuyama et al reported that Sox9 + pancreatic ductal cells were not able to give rise to β cells in PDL-treated adult mice or streptozotocin (STZ)-induced diabetic mice (16).…”

SOX4 cooperates with neurogenin 3 to regulate endocrine pancreas formation in mouse models

“…The restriction towards a terminally differentiated endocrine cell occurs progressively [10]. Endocrine differentiation requires inhibition of NOTCH signalling and transient activation of neurogenin 3 (NEUROG3) in epithelial trunk progenitor cells, and is accompanied by exit from the cell cycle and migration into the mesenchyme [11][12][13][14][15][16][17][18]. Downstream, regulators of beta cell specification include: paired box 4 (PAX4), neurogenic differentiation 1 (NEUROD1), regulatory factor X, 6 (RFX6), NK2 homeobox 2 (NKX2.2), NK6 homeobox 1 (NKX6.1) and v-maf avian musculoaponeurotic fibrosarcoma oncogene homologue A (MAFA), among others [19][20][21][22][23][24][25].…”

Adult Gland Derived Stem Cells (Gdscs); Potentials, Hurdles and Expectations

“…Combining techniques, Chung et al reported a recovery of β-cell mass within two weeks after alloxan administration when combined with PDL [115]. However, the origin of β cells in this socalled "alloxan+PDL" model was not tested through the use of genetic lineage tracing studies [116].…”