Molecular mechanisms underlying pancreatic identity and plasticity in mammalian species

Abstract

Lineage reprogramming of somatic cells to generate pancreatic β-like cells represents a promising strategy for developing a cell-based therapy to treat diabetes. The close developmental origin with the pancreas and its regenerative ability make the liver an ideal tissue source for generating new β-cells. We recently identified the transcription factor TG-interacting factor 2 (TGIF2) as a developmental regulator of the cell fate decision between liver and pancreas in the mouse. Consistently, stable lentiviral expression of TGIF2 is sufficient to promote a pancreatic progenitor state in adult mouse liver cells, by repressing the hepatic transcriptional program and initiating the pancreatic progenitor one. The studies of my Ph.D. thesis have focused on further investigating the biological function of TGIF2 in the mouse and translating these findings in human cells. Specifically, I undertook an in vivo loss-of-function approach based on the Cre/LoxP recombination system in the mouse to define the requirements of Tgif2 during pancreas embryonic development. Whole transcriptome analysis showed that TGIF2 acts as regulator of binary choices: first, it establishes and maintains pancreatic identity instead of a liver fate; secondly, it controls pancreatic endocrine lineage differentiation at expenses of the acinar one. These findings were further supported by in vitro reprogramming experiments, whereby enforced expression of human TGIF2 in human primary hepatocytes repressed the liver features and promoted the induction of a pancreatic state. Moreover, I expanded the study of TGIF2 reprogramming potentials to different cellular contexts, including fibroblast cells. Overall, the results presented in this work suggest a conserved function of TGIF2 in initiating a pancreatic program in different cellular contexts. Further comprehension of TGIF2 and the molecular mechanisms regulating pancreatic identity and cellular plasticity will ultimately lead to the development of innovative cell-based therapies to cure diabetes.