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

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.