Using the precision mouse genetic tool MADM to elucidate the role of paracrine signaling in beta cell differentiation and pancreatic morphogenesis
|Title||Using the precision mouse genetic tool MADM to elucidate the role of paracrine signaling in beta cell differentiation and pancreatic morphogenesis|
|Sponsor||Marie Skłodowska-Curie Action (MSCA)|
|Institution||University of Copenhagen|
Associated cell lines
Successful clinical trials of human islet transplantation have invigorated the diabetes research community to pursue cell replacement therapies as an eventual functional cure for Type 1 diabetes. To generate therapeutic grade beta cells by directed differentiation of hPSCs, current protocols must be adapted to faithfully reproduce the in utero mechanisms of beta cell commitment. It remains unclear, however, why only a portion of metastable Ngn3-expressing pancreatic progenitors upregulate Ngn3 and fully commit to endocrine differentiation, and how paracrine signaling events further direct these endocrine progenitors to an insulin producing fate. Answers to these questions have remained elusive because of the difficulty of observing individual cell behaviors in situ in the developing pancreas. To meet this challenge, we will adapt the cutting edge mouse genetic tool Mosaic Analysis with Double Markers (MADM) to quantitatively manipulate candidate signaling pathways in concomitantly labeled cells. We aim to identify putative markers to improve directed differentiation protocols and candidate pathways to manipulate in manufacturing robust cells that are glucose responsive and capable of secreting physiological doses of insulin.