Project ID CM-HD2023_48

ThemeCM-HD

Co Supervisor 1A School of Basic and Medical Biosciences , CGTRMWebsite

Co Supervisor 1B School of Basic and Medical Biosciences , CGTRMWebsite

Regulation of cellular plasticity in the hepato-pancreato-biliary organ system

Cellular plasticity, the ability of a cell to adopt alternative fates or acquire new identities, is relevant to diverse fields, including developmental and stem cell biology, regenerative medicine. Insights into these mechanisms could provide us with tools for enhancing regeneration, but also shed light on organogenesis and define novel cell therapies. Previous investigations in the Spagnoli group have focused on the lineage plasticity between liver and pancreas with the aim to generate insulin-producing pancreatic beta-cells starting from the liver towards a cell replacement therapy for diabetes. More recently, our work has underscored that sustained plasticity is also a key feature of hepato-pancreato-biliary (HPB) development [Willnow et al. Nature 2021]. We discovered a subpopulation of progenitors, which resides in a specialized niche in a plastic/multipotent state and contributes cells not only to the pancreas but also to the liver for an extended window of time, beyond individual lineage fate specification in the mouse. Further understanding of such population during development will elucidate programs underlying growth and regeneration of these related organs. Moreover, investigations are required to determine whether a subset of cells with similar plasticity resides in the adult HPB tissues. This PhD project builds on these findings and will investigate the properties of this newly identified progenitor population, called intermediate progenitors (IMP), in the adult liver and extra-hepatic tissues.

Objectives
• Aim 1 (Years 1/2). We aim to answer fundamental outstanding questions about the newly discovered IMP cell subtype, including its location and persistence in adult tissues, using lineage tracing experiments combined with confocal and light-sheet microcopy.
• Aim 2 (Years 2/3). We will define the identity of IMP-descendants and elucidate if any transcriptional or functional difference related to their origin are retained in adult tissues, using sc-RNASeq and data integration.
• Final year. We will complete the characterization of the molecular and functional properties of the newly IMP cells and establish a culture system to recapitulate the stem cells-derived IMP niche in a dish.

The PhD student will acquire cutting-edge techniques in stem cell culture, FACS-Sorting, confocal and light-sheet microscopy, single-cell transcriptome analyses established in the Spagnoli lab. and bioinformatics skills in the Vigilante lab.

One representative publication from each co-supervisor:

• Willnow D, Benary U, Margineanu A, Vignola ML, Konrath F, Pongrac IM, Karimaddini Z, Vigilante A, Wolf J, Spagnoli FM. Quantitative lineage analysis identifies a hepato-pancreato-biliary progenitor niche. Nature. 2021 597, pages 87–91 (2021). doi: 10.1038/s41586-021-03844-1

• Gaetano D’Amato, Ragini Phansalkar, Jeffrey A. Naftaly, Pamela E. Rios Coronado, Dale O. Cowley, Kelsey E. Quinn, Bikram Sharma, Kathleen M. Caron, Alessandra Vigilante, Kristy Red-Horse. Endocardium-to-coronary artery differentiation during heart development and regeneration involves sequential roles of Bmp2 and Cxcl12/Cxcr4. Biorxiv (https://doi.org/10.1101/2021.10.25.465773)