TY - JOUR
T1 - A method for the generation of human stem cell-derived alpha cells
AU - Peterson, Quinn P.
AU - Veres, Adrian
AU - Chen, Lihua
AU - Slama, Michael Q.
AU - Kenty, Jennifer H.R.
AU - Hassoun, Shaimaa
AU - Brown, Matthew R.
AU - Dou, Haiqiang
AU - Duffy, Caden D.
AU - Zhou, Quan
AU - Matveyenko, Aleksey V.
AU - Tyrberg, Björn
AU - Sörhede-Winzell, Maria
AU - Rorsman, Patrik
AU - Melton, Douglas A.
N1 - Funding Information:
The authors thank the following people for assistance: David Gonzalez, Ben Rosenthal, Elise Enquist, Molly Carrier and George Kenty for technical assistance; Maria Ericsson from HMS Conventional Electron Microscopy Facility for technical assistance; and all members of the Melton and Peterson laboratories for helpful discussions. Q.P.P. was supported in part by JDRF. D.A.M. is a Howard Hughes Medical Institute Investigator. This work was supported by grants from NIH NIDDK, HIRN, The Swedish Research Council, The Leona M. and Harry B. Helmsley Charitable Trust, and the generosity of the J.W. Kieckhefer Foundation, the Stephen and Barbara Slaggie Family and the Khalifa Bin Zayed Al Nahyan Foundation.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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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U2 - 10.1038/s41467-020-16049-3
DO - 10.1038/s41467-020-16049-3
M3 - Article
C2 - 32382023
AN - SCOPUS:85084400242
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2241
ER -