Pancreatic progenitor cells are multipotent stem cells originating from the developing fore-gut endoderm which have the ability to differentiate into the lineage specific progenitors responsible for the developing pancreas. They give rise to both the endocrine and exocrine cells. Exocrine cells constitute the acinar cells and the ductal cells. The endocrine cells constitute the beta cells which make insulin, alpha cells which secrete glucagon, delta cells which secrete somatostatin and the PP-cells which secrete pancreatic polypeptide. Pancreatic progenitor cells have been shown to arise from cells originating from the developing foregut during mammalian development. It has been seen in the developing embryo at stages E9.0 to E9.5 that there are a cluster of cells which give rise to the pancreas. These clusters have been characterized to show multipotent properties.
Development The pancreas is an organ of endodermal origin. The endoderm is amongst the three germ layers that make up the developing embryo. The origination of the pancreatic tissue is from the dorsal and ventral aspects of the posterior foregut. They can be observed at E9.0 to E9.5 during embryonic development. Fusion of these buds occurs during rotation of the developing gut. The fused and developed pancreas consists of pancreatic enzyme secreting cells (exocrine cells), digestive enzyme transporting cells (ductal cells) and hormone producing cells (endocrine cells). These endocrine cells develop in discrete areas within the pancreas known as the islets.
In humans, the dorsal bud can be observed 26 days post-fertilization. However, the islet cells can only be observed at 52 days post-fertilization. The development of beta cells precedes that of the development of other endocrine cells in the islets. All islet cells can be observed in the first trimester in human. This variation in the development of islet cell subtypes is due to differential gene expression and induction pathways of progenitor cells.
Progenitors in the adult pancreas In addition to the multipotent progenitors of the developing pancreas, the adult pancreas contains cells with progenitor-like properties that can contribute to the formation of new endocrine cells, particularly after injury. Studies in zebrafish using single-cell RNA sequencing have characterized ductal cell populations of the adult pancreas, including Notch-responsive ductal cells and a distinct population of krt4-expressing ductal cells that act as ductal progenitors of endocrine cells. Following the loss of beta cells, these ductal progenitors, together with subsets of endocrine cells, can give rise to new insulin-producing cells and contribute to beta-cell regeneration. Because pancreatic endocrine differentiation is broadly conserved across vertebrates, such progenitor populations are studied as models for generating beta cells in regenerative approaches to diabetes.
Locations Genetic lineage tracing experiments have been performed by various research groups to show that the cell clusters originating from the developing foregut express a transcription factor called PDX1 (Pancreatic and duodenal homeobox 1). This transcription factor has been shown to give rise to the multipotent stem cell lineages contributing to the endocrine, exocrine and ductal cells of the pancreas. These cells have been shown to be spatially located at the tip of the branching pancreatic tree. Later these cells are shown to originate from the dorsal bud of the developing pancreas. Pdx1 is accepted as the earliest marker for pancreatic differentiation. Pdx1 has been shown to be a marker for all pancreatic and mid-gut progenitor cells. Pdx1 expression is empirical to drive the developing pancreas after the bud stage where two buds (dorsal and lateral) of the immature pancreas develop. Notch signaling has been shown to regulate the number of exocrine and endocrine cells in the pancreas, but not without the presence of Pdx1. Notch signaling allows the expansion of pancreatic progenitors by the process of lateral inhibition. These cells have been shown to have 28 genes regulating the cell cycle to be upregulated, showing that they are proliferative cells having the ability to replace and give rise to multiple cell populations in the pancreas.
Regulation of specification Pancreatic progenitors have been shown to arise from the early expression of the gene Mnx1/Hlxb1 (Motor Neuron and pancreas homeobox 1). Mnx1 expression has been shown to be important for the development of dorsal Pdx1, hence acting as a necessary transcription factor for the specification of foregut endoderm into Pdx1 expressing pancreatic progenitors. Similarly, another set of genes Gata4 (GATA binding protein 4) and Hnf1b/Tcf2 (HNF homobox B gene) is required for the development of the ventral bud of the developing pancreas. These genes regulates the expression of Mnx1 in the ventral bud, leading to the developmental specification of the pancreatic progenitor cells expressing Pdx1. One gene Onecut1/Hnf6 (onecut domain family member 1 transcription factor) is also responsible for the timely expression of Pdx1 in both the ventral and dorsal buds. Hence the expression of this protein also contributes to the formation of these pancreatic progenitors expressing Pdx1. The developing dorsal and ventral buds are characterized as endoderm, and it isn't until the expression of Pdx1 (specification of endoderm to a stem cell multipotent state) that the endoderm to pancreatic progenitor transition occurs. The variable number of genes shows the multiple routes of induction of the developing endoderm, intrinsically within the endoderm (for example, notch signaling) or from the adjacent cardiac mesoderm (Sonic hedgehog protein inhibition by Fibroblast growth factor). The differential of pancreatic progenitors from hepatic progenitors is also notable, as Hhex1 (Hematopoietically expressed homeobox gene) is responsible for the origination of pancreatic progenitor cells. In the absence of Hhex, (in Hhex double negative mice) the liver develops but not the pancreas, showing that Hhex allows for divergent specification of a pancreatic progenitor rather than allow the formation of a hepatic progenitor.
Developing lineages Pancreatic progenitor cells have the ability to differentiate into both endocrine and exocrine precursors.
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