Pancreatic Exocrine Duct Cells Give Rise to Insulin-Producing β Cells during Embryogenesis but Not after Birth

Abstract

A longstanding unsettled question is whether pancreatic beta cells originate from exocrine duct cells. We have now used genetic labeling to fate map embryonic and adult pancreatic duct cells. We show that Hnf1beta+ cells of the trunk compartment of the early branching pancreas are precursors of acinar, duct, and endocrine lineages. Hnf1beta+ cells subsequent form the embryonic duct epithelium, which gives rise to both ductal and endocrine lineages, but not to acinar cells. By the end of gestation, the fate of Hnf1beta+ duct cells is further restrained. We provide compelling evidence that the ductal epithelium does not make a significant contribution to acinar or endocrine cells during neonatal growth, during a 6 month observation period, or during beta cell growth triggered by ligation of the pancreatic duct or by cell-specific ablation with alloxan followed by EGF/gastrin treatment. Thus, once the ductal epithelium differentiates it has a restricted plasticity, even under regenerative settings.

Pancreas organogenesis: From bud to plexus to gland

“…HNF1b is expressed broadly through the foregut-midgut region at E8, and in the liver and both pancreas anlagens at E9.5 (Haumaitre et al, 2005). Solar et al (2009) showed that the early HNF1b-expressing pool is multipotent and can seed all three compartments: acinar, duct, and endocrine. During the secondary transition, HNF1b expression becomes confined to the duct/endocrine bipotent progenitor domain of the central epithelial cord (the ''mature trunk epithelium'' described below), and is also duct-restricted in the postnatal or adult organ (Solar et al, 2009).…”

“…Solar et al (2009) showed that the early HNF1b-expressing pool is multipotent and can seed all three compartments: acinar, duct, and endocrine. During the secondary transition, HNF1b expression becomes confined to the duct/endocrine bipotent progenitor domain of the central epithelial cord (the ''mature trunk epithelium'' described below), and is also duct-restricted in the postnatal or adult organ (Solar et al, 2009). In the absence of HNF1b, there is the transient formation of a dorsal pancreas ud that expresses Pdx1 and Mnx1, but these progenitors fail to expand.…”

“…The central epithelial cord, or the ''trunk'' epithelial domain, contains a pool of cells with duct/endocrine bipotency (Solar et al, 2009), although it has still not been shown with rigor that individual cells are truly bipotent, in contrast to the mixed population premise (Fig. 3).…”

“…The timing of the choice to become a particular type of hormonesecreting cell, in reference to epithelial birth, delamination, and how this is regulated to ensure the appropriate colonization of the islets of Langerhans by the correct numbers of each cell type, remain mysterious and should definitely be an area of future profound discovery. The remaining non-delaminating HNF1b þ -Sox9 þ Nkx6.1 þ trunk cells are fated to become duct cells (Seymour et al, 2007;Solar et al, 2009;Schaffer et al, 2010).…”

“…Proacini also begin differentiation from the numerous distal tips of the pancreatic epithelium, and move into synthesizing high levels of acinar digestive enzymes in addition to CpaI, such as amylase, elastase, and trypsinogen (Pictet et al, 1972). After about E14.5, acinar cells are mainly generated by the duplication of existing acinar cells, and endocrine progenitor birth in the trunk domain ends by the beginning of postnatal life (Zhou et al, 2007;Solar et al, 2009). Acinar cells and endocrine cells go through a maturation process lasting into postnatal life, and there is significant postnatal expansion of endocrine cell numbers, likely linked to self-replication (Desai et al, 2007;Finegood et al, 1995;Teta et al, 2007).…”