β-Cell regeneration through the transdifferentiation of pancreatic cells: Pancreatic progenitor cells in the pancreas

Abstract

Pancreatic progenitor cell research has been in the spotlight, as these cells have the potential to replace pancreatic β-cells for the treatment of type 1 and 2 diabetic patients with the absence or reduction of pancreatic β-cells. During the past few decades, the successful treatment of diabetes through transplantation of the whole pancreas or isolated islets has nearly been achieved. However, novel sources of pancreatic islets or insulin-producing cells are required to provide sufficient amounts of donor tissues. To overcome this limitation, the use of pancreatic progenitor cells is gaining more attention. In particular, pancreatic exocrine cells, such as duct epithelial cells and acinar cells, are attractive candidates for β-cell regeneration because of their differentiation potential and pancreatic lineage characteristics. It has been assumed that β-cell neogenesis from pancreatic progenitor cells could occur in pancreatic ducts in the postnatal stage. Several studies have shown that insulin-producing cells can arise in the duct tissue of the adult pancreas. Acinar cells also might have the potential to differentiate into insulin-producing cells. The present review summarizes recent progress in research on the transdifferentiation of pancreatic exocrine cells into insulin-producing cells, especially duct and acinar cells.

Keywords: Pancreatic progenitor cells; Transdifferentiation; β‐Cell regeneration.

Figure 1

Embryonic stem cells and induced pluripotent stem cells are considered as having potency to differentiate into insulin‐producing cells. Likewise, pancreatic progenitor cells express various markers and are able to differentiate into insulin‐producing cells. Pancreatic α‐, δ‐, ε‐, duct and acinar cells also have differentiation potency.

Figure 2

Pancreatic ducts consist of duct cells, and are connected with complexes of acinar cells that secrete the enzyme through the pancreatic duct into the duodenum. These pancreatic exocrine cells are able to transdifferentiate into insulin‐producing cells under various conditions. In addition, it is known that acinar cells are differentiated into duct cells through acinar‐ductal metaplasia. EGF, epidermal growth factor; GLP‐1, glucagon‐like peptide‐1; HGF, hepatocyte growth factor; INGAP, islet neogenesis associated protein; LIF, leukemia inhibitory factor; MafA, musculoaponeurotic fibrosarcoma oncogene family protein A, MAPK, mitogen‐activated protein kinase; Ngn3, neurogenin 3; Pdx‐1, pancreatic and duodenal homeobox‐1; STAT3, signal transducer and activator of transcription 3.

Figure 3

(a) After differentiation by cotreatment with activin A (ActA) and exendin‐4 (Ex‐4) for 30 days, differentiated human duct cells were transplanted into streptozotocin (STZ)‐induced diabetic animals. Hyperglycemia (HG) was gradually reduced after transplantation of differentiated human duct cells (P < 0.05 vs STZ). (b) For the tracing of transplanted duct cells, adenovirus‐green fluorescent protein (GFP) infection was carried out before transplantation. Transplanted duct cells were detected with insulin (red) and GFP (green) 60 days after transplantation (magnification: ×400; scale bar, 100 μm).