Gastrin: A Distinct Fate of Neurogenin3 Positive Progenitor Cells in the Embryonic Pancreas

Abstract

Neurogenin3+ (Ngn3+) progenitor cells in the developing pancreas give rise to five endocrine cell types secreting insulin, glucagon, somatostatin, pancreatic polypeptide and ghrelin. Gastrin is a hormone produced primarily by G-cells in the stomach, where it functions to stimulate acid secretion by gastric parietal cells. Gastrin is expressed in the embryonic pancreas and is common in islet cell tumors, but the lineage and regulators of pancreatic gastrin+ cells are not known. We report that gastrin is abundantly expressed in the embryonic pancreas and disappears soon after birth. Some gastrin+ cells in the developing pancreas co-express glucagon, ghrelin or pancreatic polypeptide, but many gastrin+ cells do not express any other islet hormone. Pancreatic gastrin+ cells express the transcription factors Nkx6.1, Nkx2.2 and low levels of Pdx1, and derive from Ngn3+ endocrine progenitor cells as shown by genetic lineage tracing. Using mice deficient for key transcription factors we show that gastrin expression depends on Ngn3, Nkx2.2, NeuroD1 and Arx, but not Pax4 or Pax6. Finally, gastrin expression is induced upon differentiation of human embryonic stem cells to pancreatic endocrine cells expressing insulin. Thus, gastrin+ cells are a distinct endocrine cell type in the pancreas and an alternative fate of Ngn3+ cells.

The islet ghrelin cell

“…the pig (Capella et al 1978, Alumets et al 1983) and gastrinproducing G-cells have been demonstrated in the rat pancreas during neonatal development, while such cells are present, albeit in small numbers, in the pancreas of adult cat and dog (Larsson et al 1976a). Recently, G-cells have also been found to be a distinct islet cell type in mice during development (Suissa et al 2013).…”

Gastrin induces ductal cell dedifferentiation and β-cell neogenesis after 90% pancreatectomy

“…NEUROG3 expression peaks during the major endocrine cell differentiation phase of the embryonic pancreas, known as 'secondary transition'. During this period gastrin and its high-affinity receptor cholecystokinin B receptor (CCKBR) are expressed within the endocrine domain of the developing pancreas (Larsson et al 1976, Suissa et al 2013. In post-natal life, pancreatic gastrin and CCKBR expression declines along with b-cell neogenesis (Rooman et al 2001, Suissa et al 2013.…”

“…During this period gastrin and its high-affinity receptor cholecystokinin B receptor (CCKBR) are expressed within the endocrine domain of the developing pancreas (Larsson et al 1976, Suissa et al 2013. In post-natal life, pancreatic gastrin and CCKBR expression declines along with b-cell neogenesis (Rooman et al 2001, Suissa et al 2013. Ectopic expression of gastrin and transforming growth factor alpha in the pancreas or administration of gastrin in combination with epidermal growth factor or glucagon-like peptide 1 analogues has been shown to increase the b-cell mass and/or to improve glucose tolerance (Wang et al 1993, Rooman et al 2002, Suarez-Pinzon et al 2005, 2008a, supporting a potential role of gastrin in the treatment of diabetes.…”

Activation of GLP-1 and gastrin signalling induces in vivo reprogramming of pancreatic exocrine cells into beta cells in mice

“…Gastrin initiates beta cell neogenesis and activation of GLP-1 signalling enhances its effect Gastrin is known to be expressed in the developing pancreas whereas it is not expressed in adult pancreas [27,28], suggesting its possible role in pancreatic endocrine development. To investigate whether or not gastrin can induce beta cell neogenesis in the adult pancreas, exo-lacZ and exo-Glp1r mice were treated with gastrin and exendin-4 using the same protocol as above (Fig.…”

“…Gastrin is expressed in the developing pancreas, particularly in endocrine populations [27,28]. Although several reports have shown that combination therapy with gastrin and growth factors, such as EGF and TGF-α, increased beta cell mass [41][42][43][44][45], there was no evidence that gastrin could induce beta cell neogenesis as distinguished from beta cell replication.…”