CV Science

Patrick Collombat Ph.D

Course and current status

Scientific summary

The pancreas plays a major role in nutritional homeostasis through synthesis and secretion of hormones and enzymes. This organ includes endocrine and exocrine cell types, all deriving from a common set of epithelial cells that originate in the early gut endoderm. The exocrine pancreas develops to form acinar cells and a highly branched ductal epithelium, while endocrine cells aggregate into islets of Langerhans. The latter correspond to specialized micro-organs composed of four different cell types: alpha-, beta-, delta-, and PP-cells, which produce the hormones glucagon, insulin, somatostatin, and PP (pancreatic polypeptide), respectively. Insulin and glucagon function coordinately to control glucose homeostasis, whereas somatostatin and PP regulate the secretion of other hormones and of exocrine enzymes (for review, see Collombat et al., 2006).

Understanding how beta-cells are generated during development, but also throughout adulthood, is a prerequisite to the design of regenerative and cellular therapies for type 1 and type 2 diabetes, both diseases being ultimately characterized by loss and/or insufficient numbers of beta-cells. Towards this goal, the characterization of the genetic determinants underlying endocrine pancreas morphogenesis has demonstrated that, during the course of development, the cooperation of several transcription factors successively specifies progenitor cells towards the pancreatic-, endocrine- and ultimately islet-cell fates (Collombat et al., 2006). Hence, Pdx1 is required for pancreatic epithelium (Ahlgren et al., 1996) and subsequently Neurogenin3 (Ngn3) for endocrine lineage specification (Gradwohl et al., 2000). Next to Ngn3 induction, a complex network of transcription factors progressively and differentially promotes the four endocrine cell lineages, including the homeodomain-containing Arx and Pax4 factors (Collombat, 2003; Sosa-Pineda et al., 1997). Interestingly, in the absence of Arx, the beta and delta-cell fates were found favoured at the expense of alpha-cell genesis, while the total endocrine cell content remained normal (Collombat, 2003). Conversely, in mice lacking Pax4, the opposite phenotype was observed (increased alpha-cell content, lack of beta- and delta-cells), indicating an inhibitory, cross-regulatory circuit between Arx and Pax4 (Collombat, 2003). Additional findings supported these conclusions and suggested that, firstly, Arx and Pax4 instruct endocrine precursor cells towards either an alpha- or a beta-/delta-cell fate, respectively. Next, through the analysis of double-mutant mice (Collombat, 2005), a secondary function of Pax4 in specifying the beta-cell lineage in beta-/delta-precursor cells was uncovered.

Using a conditional expression approach, recent evidence demonstrated that the misexpression of Arx in early pancreatic cells drives endocrine precursors towards either an alpha- or, surprisingly, a PP-cell fate (Collombat et al., 2007). Arx is thus not only necessary, but also sufficient to instruct the alpha- and PP-cell lineages. Of particular interest was the finding that the misexpression of Arx triggered in adult beta-cells induces their conversion into cells exhibiting alpha- or PP-cell characteristics (Collombat et al., 2007). This discovery was of fundamental importance in the context of beta-cell-based therapy as it implied that the opposite conversion might be achieved, that is, to generate beta-cells from other endocrine cells. To test this hypothesis, using the Cre/Lox system, we generated mice conditionally misexpressing the Pax4 gene. We demonstrated that the ectopic expression of Pax4 in the developing mouse pancreas results in oversized islets mostly composed of cells displaying a beta-cell phenotype (Collombat, 2009). Interestingly, we provided evidence that the misexpression of Pax4 in glucagon expressing-cells converts these into cells exhibiting most features of true beta-cells. Our findings were consistent with a continuous activation of facultative progenitor cells located near the lining of ducts that reactivate Ngn3 expression (Xu et al., 2008), adopt a glucagon-producing cell identity as a consequence of decreased glucagon levels, and subsequently acquire a beta-cell phenotype upon Pax4 misexpression. The resulting lineage-traced beta-like cells generated through this cycle of neogenesis/redifferentiation were functional, at least at an early age, and could repopulate islets depleted in beta-cells in vivo, and thereby reverse chemically-induced type 1 diabetes (Collombat, 2009).

Our current approaches consist in gaining further insight into the molecular mechanisms that underly the alpha-to-beta-cell transdifferentiation and inducing it with chemical compounds (Ben-Othman, 2017). 

Honours: 

• Appointed Knight in the National Order of Merit (2018 - French president) 
• Auguste Loubatières Award (2015 - French Society of Diabetes)
• Morgagni Prize (2014 - Servier)
• Medal of Honour (2013 - General council of Nice)
• Fondation Générale de Santé Award (2013 - French academy of sciences) 
• Apollinaire Bouchardat Award (2013 - Novonordisk)
• ERC Starting Grant (2011 - European Research Council)
• Team Evaluated A+ by an International Review Panel (AERES) 
• Career Development Award (2010 - Juvenile Diabetes Research Fundation) 
• Schlumberger Fundation Award (2009 - Schlumberger Fundation) 
• Avenir Excellency Financing (2009 - INSERM)