Neogenesis of Pancreatic Endocrine Cells in Copper-Deprived Rat Models

Abstract

Transplantation of progenitor cells for regeneration of islet cells could prove invaluable in the treatment of diabetes mellitus. This study provides evidence that in rats maintained on a copper-deficient diet containing the copper-chelating agent tetraethylenepentamine pentahydrochloride, regeneration of single alpha and beta endocrine cells in the ductules and acinar tissue of the adult rat pancreata occurred. These regenerated cells both in the ductules and acinar tissue stained positive for glucagon and insulin similar to cells within the islets and in addition to being reactive to proliferative cellular nuclear antigen, an intracellular marker of active proliferation. In contrast, the control group pancreata did not show any evidence of islet regeneration, proliferation, or proliferative cellular nuclear antigen reactivity pre- or posttransplantation. Transplantation of digested pancreatic tissues from the copper-deficient group into the spleen of syngeneic diabetic rats reversed diabetes, and this was confirmed histologically by demonstrating cells within ductules that stained positively for insulin. This study concludes that copper deprivation contributes to the neogenesis of pancreatic alpha and beta cells in the ductules and acinar tissue of adult pancreas in rat model and that transplanted stem cells maintain their functional capacity in the recipient after transplantation.

The Effect of Multispecies Probiotic Supplementation on Iron Status in Rats

“…Cu pancreas deficiency results in pancreas atrophy [44] and beta-cell neogenesis [48]. Cu deficiency has been demonstrated to induce pancreatic islet hyperplasia and hepatic metaplasia in the pancreas [49].…”

Microarray Analysis of Rat Pancreas Reveals Altered Expression of Alox15 and Regenerating Islet-Derived Genes in Response to Iron Deficiency and Overload

“…Pancreatic atrophy is observed during pancreatitis, a state which promotes extensive expression of Reg family genes [51]. Also, during copper deficiency islet hyperplasia and beta-cell neogenesis have been documented [52] in line with the islet-regenerating properties of Reg proteins. More research is needed to determine if low copper levels induce the expression of these genes.…”

Progenitor cells in the adult pancreas

“…Neogenesis of β‐cells in the adult pancreas has been observed in normal post‐natal development 81, and has been documented in experimental models of pancreas damage 53–62. This infers the presence of cells with progenitor or stem characteristics in the adult pancreas.…”

“…Animal models in which pancreatic endocrine and exocrine regeneration can be observed include chemically induced models of pancreatic injury following administration of alloxan 54, 55, streptozotocin 56 or caerulein 57, dietary copper deprivation 58, physical disruption of pancreatic duct function by cellophane wrapping of the organ 59, 60 or ligation of the pancreatic duct 53, hemipancreatectomy 61, 62 and local over‐expression of Reg1 63, IFN γ 64, 65 or TGF‐α 66, in addition to the autoimmune non‐obese diabetic (NOD) mouse model of spontaneous type 1 diabetes 67. Although the triggers may differ, in each of these models pancreatic regeneration is thought to occur through the expansion of progenitor cells present either in, or closely associated with, the ductal epithelium.…”