Exocrine ontogenies: on the development of pancreatic acinar, ductal and centroacinar cells

Abstract

This review summarizes our current understanding of exocrine pancreas development, including the formation of acinar, ductal and centroacinar cells. We discuss the transcription factors associated with various stages of exocrine differentiation, from multipotent progenitor cells to fully differentiated acinar and ductal cells. Within the branching epithelial tree of the embryonic pancreas, this involves the progressive restriction of multipotent pancreatic progenitor cells to either a central "trunk" domain giving rise to the islet and ductal lineages, or a peripheral "tip" domain giving rise to acinar cells. This review also discusses the soluble morphogens and other signaling pathways that influence these events. Finally, we examine centroacinar cells as an enigmatic pancreatic cell type whose lineage remains uncertain, and whose possible progenitor capacities continue to be explored.

Figure 1. Transcription factor expression in adult ductal epithelium

Immunofluorescent labeling for Sox9, Hnf6 and Hnf1β in adult mouse pancreas. Note heterogeneous expression, with neighboring cells often displaying different patterns of transcription factor expression.

Figure 2. Transcription factor topologies in developing mouse pancreas

Immunofluorescent labeling for Pdx1, Sox9, Nkx6.1, Ptf1a, Ngn3 and E-cadherin (Ecad) in emerging trunk and tip domains of developing mouse pancreas. Hnf1β and Nkx6.1 become progressively restricted to the central trunk region of the branching pancreatic epithelium, from which Ngn+ cells begin to emerge. In contrast, Ptf1a is restricted to peripheral tips. As late as E13.5, Pdx1 and Sox9 are expressed in both central trunk and and peripheral tip domains.

Figure 3. Emergence of ductal, islet and acinar lineages from progressively restricted trunk and tip progenitor cells

Initially tri-potent multil-ineage progenitor cells (MPCs) expressing both Pdx1 and Ptf1a ultimately give rise to ductal, islet and and acinar cells. On E11.5 most MPCs also co-express Sox9, Hnf1 β, Hnf6, Nkx6.1, and Nkx6.2. By E12.5, Hnf1 β, Hnf6, Nkx6.1, and Nkx6.2 become largely restricted to trunk progenitor cells (TrunkPCs), while Ptf1a becomes restricted to tip progenitors (TipPCs), with Notch signaling promoting the TrunkPC identity. By E13.5, acinar and lslet differentiation have been initiated, associated with the activation of additional lineage-specific transcription factors. Among TrunkPCs, Notch activation promotes a ductal fate. By the time of gestation, active Notch signaling is largely confined to centroacinar cells (CAC), whose derivation from Trunk vs. TipPCs remains unknown. CACs may be derived from either trunk progenitors maintaining active Notch signaling or from tip progenitors reactivating Notch.