Pancreas cell fate

Abstract

Diabetes is characterized by decreased function of insulin-producing insulin β cells and insufficient insulin output resulting from an absolute (Type 1) or relative (Type 2) inadequate functional β cell mass. Both forms of the disease would greatly benefit from treatment strategies that could enhance β cell regeneration and/or function. Successful and reliable methods of generatingβ cells or whole islets from progenitor cells in vivo or in vitro could lead to restoration of β cell mass in individuals with Type 1 diabetes and enhanced β cell compensation in Type 2 patients. A thorough understanding of the normal developmental processes that occur during pancreatic organogenesis, e.g., transcription factors, cell signaling molecules, and cell-cell interactions that regulate endocrine differentiation from the embryonic pancreatic epithelium, is required in order to successfully reach these goals. This review summarizes our current understanding of pancreas development, with particular emphasis on factors intrinsic or extrinsic to the pancreatic epithelium that are involved in regulating the development and differentiation of the various pancreatic cell types. We also discuss the recent progress in generating insulin-producing cells from progenitor sources.

Connective tissue growth factor acts within both endothelial cells and β cells to promote proliferation of developing β cells

“…The pancreatic vascular endothelium secretes paracrine factors important for pancreas differentiation (5)(6)(7)(8). Factors such as retinoic acid, FGFs, and bone morphogenetic proteins (BMPs) regulate the outgrowth of the epithelium, as well as the differentiation of multipotent pancreatic progenitors (9). Signals from the dorsal aorta are necessary for growth of the dorsal pancreas as well as expression of Ptf1a, a transcription factor essential for the development of pancreatic progenitors (7,10).…”

Transcription factor regulation of pancreatic organogenesis, differentiation and maturation

“…14 Pan-creatic development has been characterized as a series of bifurcating lineage decisions: endoderm vs. mesoderm and ectoderm; pancreas vs. duodenum; exocrine vs. endocrine; and b-cell vs. other hormone-positive cell types. 15 At e9.5, the pancreas originates from the foregut endoderm as 2 independent pancreatic buds, along the dorsal and ventral axis. 16 The dorsal bud is first detected at e9.0 while its complement, the ventral bud, develops at e9.5.…”

“…The individual differentiated endocrine cells delaminate, migrate into the neighboring exocrine tissue and assemble into cell clusters to initiate the formation of mature islets. 15,39 In the mouse, b-cells form a central islet core with a-, d-and PP-cells at the periphery and a small proportion of e-cells scattered throughout the islet. 40,41 …”

Differentiation into Endoderm Lineage: Pancreatic differentiation from Embryonic Stem Cells

“…The definitive endoderm-derived primitive gut tube induces the pharynx, esophagus, stomach, duodenum, small and large intestine along the anterior-posterior axis as well as associated organs, including pancreas, lung, thyroid, thymus, parathyroid, and liver (3,19). The anterior portion of the foregut of the primitive gut tube becomes lung, thyroid, esophagus, and stomach.…”

“…The more physiological treatment is replacement of β cells by whole pancreas or transplantation of islets of Langerhans from human donors, however, it is a great obstacle of transplantation that the donor of pancreatic tissue is rare. Researchers are trying to develop the ways to generate replacement sources of pancreatic β cells for cell therapy and some of the studies involve the directed differentiation of embryonic stem (ES) cells to pancreas development into glucose-responsive β cells (3). It has been achieved by progressive instructive differentiation through each of the developmental stages (4,5).…”