Research Focus
Cell fate decisions of pancreas progenitor and stem cells
We are interested in understanding how extracellular signals and intrinsic genetic programs interact to dictate cell fate decisions in stem and progenitor cells of the pancreas. The main focus is the development of the endocrine lineage in the pancreas and the function of adult pancreas stem cells in homeostasis and disease. Key questions that we are addressing concern the signals that guide cell transitions during 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 a rare population of the adult pancreas. Aldh1b1 elimination during development accelerates differentiation and compromises functionality of the adult beta cells. We have recently shown that the centroacinar Aldh1b1 expressing cells of the adult pancreas are adult stem cells necessary and sufficient for the generation of adult pancreatic organoids. Strikingly, there is an absolute requirement of Aldh1b1 function for the development of Kras driven pancreactic cancer implicating these cells in the pathogenesis of pancreatic cancer.
Future Projects and Goals
- Identify distinct signaling requirements for the generation of different pancreatic lineages
- Understand the metabolic requirements for the maintenance and specification of pancreatic progenitor cells
- Elucidate the differentiation pathways of adult pancreas stem cells during homeostasis and their role in disease
- Identify the adult pancreas stem cells in humans for the development of organoids containing all three pancreatic lineages
- Use directed differentiation of human pluripotent stem cells into beta cells to understand human endocrine development and develop cell therapies for diabetes