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. The main focus is the development of the endocrine lineage in the pancreas and the conversion of pluripotent stem cells into functional beta cells.
We have modeled two processes of interest, the development of the pancreas endocrine lineage and the specification of a motor neuron population in the mammalian hindbrain using directed differentiation of mouse ES cells and inducible expression of selected transcription factors. 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 a rare population of the adult pancreas. Aldh1b1 elimination during development accelerates differentiation and compromises functionality of the adult beta cells. On the other hand, the rare Aldh1b1 expressing cells, in the adult pancreas, have stem cell features suggesting that this gene mediates self-renewal of pancreas progenitors. Such findings are being exploited for the efficient conversion of human pluripotent stem cells into beta cells.
Future Projects and Goals
- Identify distinct signaling requirements for the different pancreatic lineages
- Isolate and functionally analyze the adult pancreas stem cells
- 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.