CURRENT PROJECTS
Lineage decision between liver and pancreas
Our recent work has contributed to the understanding of early hepato-pancreatic development by defining transcriptional and signaling signatures underlining the lineage divergence of liver and pancreas (Rodriguez-Seguel et al. Genes Dev 2013; Kofent et al. Development 2016; Escot et al. Nat Comms 2018; Ruzittu et al. Cold Spring Harb Perspect Biol. 2020). Using a combination of genetic lineage tracing, quantitative analysis, and mathematical modeling approaches we unveiled extended cellular plasticity within the hepato-pancreatic pool during lineage segregation (Willnow et al. Nature 2021). Ongoing work is aimed at elucidating the contribution of such cellular plasticity during adult organ homeostasis and diseases.
Interplay between pancreatic epithelium and surrounding microenvironment(s)
During development pancreatic epithelial cells engage in concomitant morphogenetic and fate specification events that will give rise to the final organ architecture and functions. Cues from the surrounding microenvironment are known to influence the behavior of epithelial progenitors and orchestrate these concomitant events throughout pancreas development (Petzold et al. Development 2013; Cozzitorto, Spagnoli, Curr Top Dev Biol. 2019; Cozzitorto et al. Dev Cell 2020; Willnow et al. Development 2022; Darrigrand et al. Dev Cell 2024). ). Ongoing work in the lab. focuses on the composition of the pancreatic microenvironment and the interplay between components of the surrounding microenvironment and the epithelium.
Lineage Reprogramming to generate pancreatic beta-cells
Learning how to reprogram cell identity not only holds tremendous potential for regenerative medicine, but also represents an excellent platform for elucidating developmental biology. In my lab, we have defined a novel strategy for reprogramming mouse liver cells into pancreas progenitors based on one developmental regulator of this fate decision (Heinrich et al Nat Cell Biol. 2015; Cerda-Esteban et al. Nat Comms. 2017). This represents a powerful platform for investigating mechanistic aspects of cellular identity and plasticity and provides a starting point for production of human pancreatic beta-cells for therapeutic use in patients.
iPSC modelling of human pancreatic development
Maintenance of cellular identity is required to continuously support adult organ function and prevent diseases. We study molecular defects in human β-cell development and dysfunction and how β-cell de-differentiation might result into disease (Gong et al 2013; Simaite et al. Diabetes 2015; Kofent et al. Semin Cell Dev Biol. 2016; Mueller et al. Nat Comms. 2024).