ENDOPANC

Novel signals guiding endodermal progenitor cells toward a pancreatic fate

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 Obiettivo del progetto (Objective)

'A fundamental question in developmental biology is how a specialized tissue or organ originates from a pluripotent precursor cell in the embryo. The central aim of my research is to understand how and when the pancreas is progressively specified during embryogenesis. The pancreas controls two crucial functions in our body: the production of digestive enzymes and the regulation of blood sugar. Although in the past decade many studies have contributed to a solid foundation for understanding pancreatogenesis, important gaps persist in our knowledge of early pancreas formation. A complete understanding of these early events will provide insight into the development of this organ, but also into incurable diseases that target the pancreas, such as diabetes. Finally, this information will generate a blueprint for developing cell-replacement therapies in the context of diabetes. My postdoctoral research has provided important insight into the early steps of pancreatic specification. Combining embryology and genomics in Xenopus laevis, I have identified a suite of early pancreatic factors that establish pancreatic fate within the pluripotent endoderm, including a novel signaling factor, that we named Shirin. Importantly, Shirin is alone sufficient to induce pancreatic fate and, notably, insulin expression in the embryo. In addition, Shirin is one of the earliest markers identified as being expressed in the forming pancreas both in frog and mouse embryos. To address the relevance of Shirin in the context of mammalian development and understand its mechanism of action and epistatic relations within the previously known pancreatic network, I plan to: (i) In vivo study the role of Shirin in the mouse developing pancreas by loss-of-function approach; (ii) In vitro study the potential role of Shirin in triggering differentiation towards pancreatic fate using mouse embryonic stem cells, as powerful system for in vitro dissection of mammalian embryonic development.'

Introduzione (Teaser)

Addressing the fundamental question of organ development was the subject of investigation of a European research group. Focusing on pancreas development, the EU-funded study worked to elucidate the role of a specific transcription factor.

Descrizione progetto (Article)

Organ development in the embryo occurs through a small population of progenitor cells through largely unexplored mechanisms. Identification of the molecular determinants of these processes could be explored in regenerative medicine for restoring organ structure and function.

The major role of the pancreas in human physiology is emphasised in diabetes, where the lack of insulin disturbs carbohydrate and fat metabolism. Scientists on the EU-funded 'Novel signals guiding endodermal progenitor cells toward a pancreatic fate' (ENDOPANC) project set out to dissect the mechanisms responsible for pancreatic cell specification and organogenesis. The long-term plan was to utilise this information towards the development of novel therapeutic modalities for diabetes.

Previous work by ENDOPANC researchers revealed that the transcription factor Shirin drives pancreatic cell fate during the early steps of pancreas development in both the mouse and the frog. Ablation of this molecule in transgenic mice disrupted epithelial morphogenesis and led to organ hypoplasia during pancreas development. Investigation of the metabolic phenotype of these animals demonstrated reduced insulin production and glucose intolerance.

In another part of the project, ENDOPANC scientists used mouse embryonic stem (ES) cells to induce differentiation down the pancreatic cell lineage. Studying the lineage-specific developmental program in the presence of Shirin would help determine the role of this transcription factor. The ES in vitro model system would also facilitate future biochemical analyses aimed at the understanding of the mechanism of this novel pancreatic factor.

Collectively, the work by the ENDOPANC team provided fundamental knowledge on the process of pancreatic development. From a diabetes perspective, this information could be utilised in cell-based therapies for obtaining progenitor cells or insulin-producing pancreatic beta cells.