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Genetic programming of liver and pancreas progenitors: lessons for stem-cell differentiation

Nature Reviews Genetics volume 9, pages 329–340 (2008)Cite this article

Key Points

  • The liver and pancreas both arise from a multipotent population of endoderm cells and share many characteristics of their early development, including the expression of common regulatory transcription factors.

  • There are different natural mechanisms for generating the liver and pancreas, as can be observed — each tissue originates from multiple spatial domains of endoderm cells and is under the influence of different genes and inductive cues. The diversity of natural mechanisms for generating liver and pancreas progenitors is anticipated to enable flexibility in programming liver and pancreas cells (for example, hepatocytes and insulin cells) from other progenitor and stem-cell types.

  • During regenerative responses to tissue damage, rare progenitor cells emerge in the liver and pancreas and help to repopulate the tissue. However, we lack the means to prospectively identify such progenitors and follow their activation and development. But in certain animal models, mutations of transcription-factor genes lead to reproducible fate changes that can be monitored prospectively, providing the opportunity to study fundamental mechanisms of fate determination and cellular plasticity.

  • Gene regulatory networks appear to be simple and involve fewer feedback loops early in liver development, compared with later in development. It is thought that the more complex networks that involve feedback regulation by transcription factors could account for the more stable phenotype of mature cells.

  • Genetic studies using mouse embryo chimeras and conditional cell ablation have shown that the remarkable regenerative capacity of the liver is established at the earliest stages of hepatoblast development, and that the more limited regenerative capacity of the pancreatic endocrine cells is also established at the earliest stages of pancreas development. Understanding how these differences are manifested so early might provide powerful clues about how to control regenerative capacity.

  • Although, in the past, mammalian systems have provided the most information about the basis for liver and pancreas development, the genetic and molecular facility of model organisms such as zebrafish, Xenopus leavis and the chick are beginning to outpace embryonic studies of mammalian liver and pancreas development. This is exemplified by the extensive and detailed role of Wnt signalling in liver specification as revealed by forward genetic screens for liver defects in zebrafish and by the ability to readily inactivate genes by RNA inerference in X. leavis embryos.

Abstract

The liver and pancreas arise from a common multipotent population of endoderm cells and share many aspects of their early development. Yet each tissue originates from multiple spatial domains of the endoderm, under the influence of different genes and inductive cues, and obtains different regenerative capacities. Emerging genetic evidence is illuminating the ability of newly specified hepatic and pancreatic progenitors to reverse their course and develop into gut progenitors. Understanding how tissue programming can be reversed and how intrinsic regenerative capacities are determined should facilitate the discovery of the basis of cellular plasticity and aid in the targeted programming and growth of stem cells.

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Figure 1: Developmental origins of the liver and pancreas.
Figure 2: Gene regulatory networks for specifying ventral and dorsal pancreas progenitors.
Figure 3: Liver induction differences between model organisms.
Figure 4: Developmental plasticity in the liver and pancreas lineages.

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Acknowledgements

The author thanks D. Freedman-Cass for comments on the manuscript and E. Pytko for help in preparing the manuscript. Work in the author's laboratory is supported by grants from the National Institutes of Health, including from the Institutes of General Medical Sciences; Diabetes, Digestive, and Kidney Diseases; and Cancer; as well as from the Mathers Charitable Foundation and the W. W. Smith Charitable Trust.

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  1. Epigenetics and Progenitor Cells Program, Fox Chase Cancer Center, Room W410, 333 Cottman Avenue, Philadelphia, 19111, Pennsylvania, USA

    Kenneth S. Zaret

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Glossary

Endoderm

One of the three primary germ layers (including mesoderm and ectoderm) that result from embryonic gastrulation. The endoderm gives rise to the gut tissues, including the thyroid, lung, liver, pancreas, stomach and intestines.

Amniotes

Vertebrates (including reptiles, birds, and mammals) that contain an amnion — an extra-embryonic layer that secretes amniotic fluid and thus provides an aqueous environment for the embryo during early development.

Fate mapping

A procedure whereby cells are labelled with a dye or a genetic mark such that, following cell replication, both descendants will retain the label — meaning that the descendant cell types or tissues can be traced.

Ventral midline

A line of cells that extend from the anterior ventral region of the foregut to the posterior ventral region of the foregut, in amniote embryos.

Paraxial mesoderm

An early derivative of mesoderm after gastrulation; located between the notochord and the lateral plate mesoderm and gives rise to somites — transient structures that lead to vertebrae, ribs, dermis of the dorsal skin, and the skeletal muscles of the back, body wall and limbs.

Lateral plate mesoderm

One of the early derivatives of mesoderm after gastrulation; located distal to the notochord and paraxial mesoderm and gives rise to heart, blood vessels, blood cells and the lining of the body cavities.

Septum transversum mesenchyme

Mesodermal cells that are derived from the most rostral, distal portion of the lateral plate mesoderm. Septum transversum mesenchyme cells contribute to the heart, the mesentery around the liver and the thoracic diaphragm. Notably, during hepatic induction in amniotes, septum transversum mesenchyme cells help to induce liver growth and differentiation and might contribute to the endothelial population during liver vasculature development.

In vivo footprinting

A method to identify specific nucleotide sequences that are occupied by proteins in native nuclear chromatin.

Chromatin immunoprecipitation

(ChIP). A technique that isolates sequences from soluble DNA–chromatin extracts (complexes of DNA and protein) by using antibodies that recognize specific chromosomal proteins.

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Zaret, K. Genetic programming of liver and pancreas progenitors: lessons for stem-cell differentiation. Nat Rev Genet 9, 329–340 (2008). https://doi.org/10.1038/nrg2318

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