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Peterson, Quinn

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Peterson

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Peterson, Quinn
Author's Publications: search.filters.isAuthorOfPublication.d22abd48-3636-4017-89f9-27ca2ebddec2

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    Reversal of β cell de-differentiation by a small molecule inhibitor of the TGFβ pathway
    (eLife Sciences Publications, Ltd, 2014) Blum, Barak; Roose, Adam; Barrandon, Ornella; Maehr, René; Arvanites, Anthony C; Davidow, Lance; Davis, Jeffrey; Peterson, Quinn; Rubin, Lee; Melton, Douglas
    Dysfunction or death of pancreatic β cells underlies both types of diabetes. This functional decline begins with β cell stress and de-differentiation. Current drugs for type 2 diabetes (T2D) lower blood glucose levels but they do not directly alleviate β cell stress nor prevent, let alone reverse, β cell de-differentiation. We show here that Urocortin 3 (Ucn3), a marker for mature β cells, is down-regulated in the early stages of T2D in mice and when β cells are stressed in vitro. Using an insulin expression-coupled lineage tracer, with Ucn3 as a reporter for the mature β cell state, we screen for factors that reverse β cell de-differentiation. We find that a small molecule inhibitor of TGFβ receptor I (Alk5) protects cells from the loss of key β cell transcription factors and restores a mature β cell identity even after exposure to prolonged and severe diabetes. DOI: http://dx.doi.org/10.7554/eLife.02809.001
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    Charting Cellular Identity During Human in Vitro β-Cell Differentiation
    (Springer Science and Business Media LLC, 2019-05) Veres, Adrian; Faust, Aubrey; Bushnell, Henry; Engquist, Elise; Kenty, Jennifer; Harb, George; Poh, Yeh-Chuin; Sintov, Elad; Gürtler, Mads; Pagliuca, Felicia; Peterson, Quinn; Melton, Douglas
    In vitro differentiation of human stem cells can produce pancreatic β-cells; the loss of this insulin-secreting cell type underlies type 1 diabetes. Here, as a step towards understanding this differentiation process, we report the transcriptional profiling of more than 100,000 human cells undergoing in vitro β-cell differentiation, and describe the cells that emerged. We resolve populations that correspond to β-cells, α-like poly-hormonal cells, non-endocrine cells that resemble pancreatic exocrine cells and a previously unreported population that resembles enterochromaffin cells. We show that endocrine cells maintain their identity in culture in the absence of exogenous growth factors, and that changes in gene expression associated with in vivo β-cell maturation are recapitulated in vitro. We implement a scalable re-aggregation technique to deplete non-endocrine cells and identify CD49a (also known as ITGA1) as a surface marker of the β-cell population, which allows magnetic sorting to a purity of 80%. Finally, we use a high-resolution sequencing time course to characterize gene-expression dynamics during the induction of human pancreatic endocrine cells, from which we develop a lineage model of in vitro β-cell differentiation. This study provides a perspective on human stem-cell differentiation, and will guide future endeavours that focus on the differentiation of pancreatic islet cells, and their applications in regenerative medicine.