Anthony Gavalas Group
Stem Cells in Pancreas Development and Disease
We are interested in understanding how extracellular signals and intrinsic genetic programs interact to initially dictate cell fate decisions in stem and progenitor cells and eventually establish mature phenotypes. Our main focus is the development of the endocrine lineage in the pancreas and the conversion of human pluripotent stem cells into functional beta cells. Key questions that we are addressing concern the signals that guide cell transitions during pancreas differentiation and the regulators of the timing of these transitions.
We have identified a new signal, sphingosine-1-phosphate, which plays a conserved role in the aggregation of endocrine cells to form islets. The same signaling pathway mediates survival of acinar and endocrine progenitors and triggers their differentiation through stabilization of YAP and attenuation of Notch signaling. Additionally, we have found that Aldh1b1, encoding a mitochondrial enzyme, regulates the timing of differentiation in the developing pancreas. The gene is expressed in all pancreatic progenitors during development and in the rare centroacinar cells of the adult pancreas. Aldh1b1 elimination during development accelerated differentiation and compromised functionality of the adult beta cells. On the other hand, genetic lineage tracing showed that the rare Aldh1b1 expressing cells in the adult pancreas give rise to cells of all three pancreatic lineages during homeostasis. Strikingly, we have found that Aldh1b1 function is absolutely required for the development of pancreatic cancer. Finally, we are taking advantage of these and other findings to expand in culture pancreatic progenitors and efficiently convert human pluripotent stem cells into mature beta cells using reporter lines and inducible gene expression.
Future Projects and Goals
- Identify distinct signaling requirements for the different pancreatic lineages
- Explore the role of adult pancreas stem cells in organ homeostasis and cancer development
- Understand the metabolic requirements for the maintenance of pancreas progenitor cells
- Use directed differentiation of human pluripotent stem cells into beta cells to understand human endocrine development and develop cell therapies for diabetes
Methodological and Technical Expertise
- Generation of beta like cells from human pluripotent stem cells
- Organotypic culture of embryonic pancreas
- Organoid cultures of embryonic and adult pancreas progenitors
- All experimental approaches for molecular embryology