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A method for the generation of human stem cell-derived alpha cells

The generation of pancreatic cell types from renewable cell sources holds promise for cell replacement therapies for diabetes. Although most effort has focused on generating pancreatic beta cells, considerable evidence indicates that glucagon secreting alpha cells are critically involved in disease...

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Autores principales: Peterson, Quinn P., Veres, Adrian, Chen, Lihua, Slama, Michael Q., Kenty, Jennifer H. R., Hassoun, Shaimaa, Brown, Matthew R., Dou, Haiqiang, Duffy, Caden D., Zhou, Quan, Matveyenko, Aleksey V., Tyrberg, Björn, Sörhede-Winzell, Maria, Rorsman, Patrik, Melton, Douglas A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205884/
https://www.ncbi.nlm.nih.gov/pubmed/32382023
http://dx.doi.org/10.1038/s41467-020-16049-3
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author Peterson, Quinn P.
Veres, Adrian
Chen, Lihua
Slama, Michael Q.
Kenty, Jennifer H. R.
Hassoun, Shaimaa
Brown, Matthew R.
Dou, Haiqiang
Duffy, Caden D.
Zhou, Quan
Matveyenko, Aleksey V.
Tyrberg, Björn
Sörhede-Winzell, Maria
Rorsman, Patrik
Melton, Douglas A.
author_facet Peterson, Quinn P.
Veres, Adrian
Chen, Lihua
Slama, Michael Q.
Kenty, Jennifer H. R.
Hassoun, Shaimaa
Brown, Matthew R.
Dou, Haiqiang
Duffy, Caden D.
Zhou, Quan
Matveyenko, Aleksey V.
Tyrberg, Björn
Sörhede-Winzell, Maria
Rorsman, Patrik
Melton, Douglas A.
author_sort Peterson, Quinn P.
collection PubMed
description The generation of pancreatic cell types from renewable cell sources holds promise for cell replacement therapies for diabetes. Although most effort has focused on generating pancreatic beta cells, considerable evidence indicates that glucagon secreting alpha cells are critically involved in disease progression and proper glucose control. Here we report on the generation of stem cell-derived human pancreatic alpha (SC-alpha) cells from pluripotent stem cells via a transient pre-alpha cell intermediate. These pre-alpha cells exhibit a transcriptional profile similar to mature alpha cells and although they produce proinsulin protein, they do not secrete significant amounts of processed insulin. Compound screening identified a protein kinase c activator that promotes maturation of pre-alpha cells into SC-alpha cells. The resulting SC-alpha cells do not express insulin, share an ultrastructure similar to cadaveric alpha cells, express and secrete glucagon in response to glucose and some glucagon secretagogues, and elevate blood glucose upon transplantation in mice.
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spelling pubmed-72058842020-05-13 A method for the generation of human stem cell-derived alpha cells Peterson, Quinn P. Veres, Adrian Chen, Lihua Slama, Michael Q. Kenty, Jennifer H. R. Hassoun, Shaimaa Brown, Matthew R. Dou, Haiqiang Duffy, Caden D. Zhou, Quan Matveyenko, Aleksey V. Tyrberg, Björn Sörhede-Winzell, Maria Rorsman, Patrik Melton, Douglas A. Nat Commun Article The generation of pancreatic cell types from renewable cell sources holds promise for cell replacement therapies for diabetes. Although most effort has focused on generating pancreatic beta cells, considerable evidence indicates that glucagon secreting alpha cells are critically involved in disease progression and proper glucose control. Here we report on the generation of stem cell-derived human pancreatic alpha (SC-alpha) cells from pluripotent stem cells via a transient pre-alpha cell intermediate. These pre-alpha cells exhibit a transcriptional profile similar to mature alpha cells and although they produce proinsulin protein, they do not secrete significant amounts of processed insulin. Compound screening identified a protein kinase c activator that promotes maturation of pre-alpha cells into SC-alpha cells. The resulting SC-alpha cells do not express insulin, share an ultrastructure similar to cadaveric alpha cells, express and secrete glucagon in response to glucose and some glucagon secretagogues, and elevate blood glucose upon transplantation in mice. Nature Publishing Group UK 2020-05-07 /pmc/articles/PMC7205884/ /pubmed/32382023 http://dx.doi.org/10.1038/s41467-020-16049-3 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Peterson, Quinn P.
Veres, Adrian
Chen, Lihua
Slama, Michael Q.
Kenty, Jennifer H. R.
Hassoun, Shaimaa
Brown, Matthew R.
Dou, Haiqiang
Duffy, Caden D.
Zhou, Quan
Matveyenko, Aleksey V.
Tyrberg, Björn
Sörhede-Winzell, Maria
Rorsman, Patrik
Melton, Douglas A.
A method for the generation of human stem cell-derived alpha cells
title A method for the generation of human stem cell-derived alpha cells
title_full A method for the generation of human stem cell-derived alpha cells
title_fullStr A method for the generation of human stem cell-derived alpha cells
title_full_unstemmed A method for the generation of human stem cell-derived alpha cells
title_short A method for the generation of human stem cell-derived alpha cells
title_sort method for the generation of human stem cell-derived alpha cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205884/
https://www.ncbi.nlm.nih.gov/pubmed/32382023
http://dx.doi.org/10.1038/s41467-020-16049-3
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