A Multipotent Progenitor Domain Guides Pancreatic Organogenesis

Abstract

The mammalian pancreas is constructed during embryogenesis by multipotent progenitors, the identity and function of which remain poorly understood. We performed genome-wide transcription factor expression analysis of the developing pancreas to identify gene expression domains that may represent distinct progenitor cell populations. Five discrete domains were discovered. Genetic lineage-tracing experiments demonstrate that one specific domain, located at the tip of the branching pancreatic tree, contains multipotent progenitors that produce exocrine, endocrine, and duct cells in vivo. These multipotent progenitors are Pdx1(+)Ptf1a(+)cMyc(High)Cpa1(+) and negative for differentiated lineage markers. The outgrowth of multipotent tip cells leaves behind differentiated progeny that form the trunk of the branches. These findings define a multipotent compartment within the developing pancreas and suggest a model of how branching is coordinated with cell type specification. In addition, this comprehensive analysis of >1,100 transcription factors identified genes that are likely to control critical decisions in pancreas development and disease.

Pancreas organogenesis: From bud to plexus to gland

“…The tip cells retain expression of the ''primary multipotency markers'' Pdx1 and Ptf1a, and have the molecular signature of Pdx1 þ Ptf1a þ CpaI þ cMyc HI . Genetic lineage tracing studies performed using CpaI-CreER (here the enzyme gene Cpa1 could be considered a surrogate for Ptf1a, because Ptf1a regulates its expression) showed that tip cells at E12.5 produce all pancreatic cell types (endocrine, duct, acini), confirming their MPC nature (Zhou et al, 2007).…”

“…For example, how the simplified tip-trunk model (Zhou et al, 2007; Fig. 2A) fits into this emerging structure might require a large-scale, detailed 3-dimensional mapping effort, paying specific attention to the stage of pancreas development, and the general and precise geographic location within the expanding epithelial arbor.…”

“…Another point raised by Villasenor et al (2010) is the large expansion of the duct/endocrine ''trunk epithelium'' that they proposed to occur not by end-specific outgrowth extension, but by a process involving broadly distributed (both internal and peripheral) tip-splitting, lateral expansion and monolayer remodeling It is possible that the ''MPC tip cells'' in, for example, Zhou et al (2007) were simply being focused on as the more peripheral population of these structures. A tip splitting-remodeling mechanism would be an attractive way of rapidly expanding the duct/endocrine containing ''trunk epithelium'' over the middle and later stages of pancreas organogenesis (including the secondary transition), while producing the massive numbers of future tip acinardirected cells (we refer the reader to figure 2F in Villasenor et al, 2010).…”

“…For a limited time, tip MPC proliferation extends the arbor and drives remodeling of the epithelium, pushing the epithelial tips outward and leaving behind trunk-specified cells that possibly have a slower division rate (Zhou et al, 2007) (Fig. 2A).…”

“…This distinction is now becoming defined better on the basis of molecular markers, including some of the transcription factors that are responsible for dictating the gene expression programs and fates of the cells in these regions. While the tip domains contain multipotential pancreatic cells (MPC), which are then believed to change into acinar-fated progenitors, the adjacent trunk epithelial region consists of an endocrine-duct bipotential progenitor pool (Zhou et al, 2007) (Fig. 2A).…”