Final Report Summary - HEPATOPANCREATIC (MECHANISMS UNDERLYING CELL FATE DECISION BETWEEN PANCREAS AND LIVER)
Diabetes is a degenerative disease affecting millions of persons worldwide. Reprogramming of somatic cells into pancreatic beta-cells represents a promising strategy for cell-based therapy of diabetes. The liver is an ideal tissue source for generating new beta-cells, due to its close developmental origin with the pancreas and regenerative ability. However, how pancreatic versus hepatic fate decision occurs during development and the molecular basis for hepatic-pancreatic cellular plasticity are still poorly understood.
Elucidating the origin of the pancreas and liver divergence at the cellular and molecular level has been the central focus of the HEPATOPANCREATIC ERC-funded project (ERC St_Grant # 243045) in the past 5 years. Overall, the HEPATOPANCREATIC project has achieved the ambitious goals set out in the original proposal.
We used RNA-Seq systematically to define the molecular identity of liver and pancreas progenitor cells during the period of their lineage divergence in the mouse embryo (E8.5-E10.5). First, we developed a strategy for FACS-based purification of liver and pancreas progenitors from Prox1-EGFP transgenic mouse embryos and then performed RNA-Seq to explore their transcriptomes at distinct developmental stages, before and after the onset of organogenesis. By integrating the temporal and spatial gene expression profiles, we defined potential regulators of the cell fate divergence between the pancreas and liver. Subsequently, we set up ex vivo and in vivo models for targeted functional studies of developmental regulators of the pancreas and/or liver fate and their potentials to promote liver cell reprogramming towards pancreatic beta-cell lineage.
In conclusion, the HEPATOPANCREATIC project has provided novel insights into cellular plasticity and the basis for formulating reprogramming strategies between liver and pancreatic cells. Finding of the HEPATOPANCREATIC research opens new and important scientific and technological horizons for the EU and society, having direct implications in the development of cell-based therapy approaches for diabetes.
Elucidating the origin of the pancreas and liver divergence at the cellular and molecular level has been the central focus of the HEPATOPANCREATIC ERC-funded project (ERC St_Grant # 243045) in the past 5 years. Overall, the HEPATOPANCREATIC project has achieved the ambitious goals set out in the original proposal.
We used RNA-Seq systematically to define the molecular identity of liver and pancreas progenitor cells during the period of their lineage divergence in the mouse embryo (E8.5-E10.5). First, we developed a strategy for FACS-based purification of liver and pancreas progenitors from Prox1-EGFP transgenic mouse embryos and then performed RNA-Seq to explore their transcriptomes at distinct developmental stages, before and after the onset of organogenesis. By integrating the temporal and spatial gene expression profiles, we defined potential regulators of the cell fate divergence between the pancreas and liver. Subsequently, we set up ex vivo and in vivo models for targeted functional studies of developmental regulators of the pancreas and/or liver fate and their potentials to promote liver cell reprogramming towards pancreatic beta-cell lineage.
In conclusion, the HEPATOPANCREATIC project has provided novel insights into cellular plasticity and the basis for formulating reprogramming strategies between liver and pancreatic cells. Finding of the HEPATOPANCREATIC research opens new and important scientific and technological horizons for the EU and society, having direct implications in the development of cell-based therapy approaches for diabetes.