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Efficient Generation of Glucose-Responsive Beta Cells from Isolated GP2+ Human Pancreatic Progenitors

Ameri, Jacqueline LU ; Borup, Rehannah; Prawiro, Christy; Ramond, Cyrille; Schachter, Karen A. LU ; Scharfmann, Raphael and Semb, Henrik LU (2017) In Cell Reports 19(1). p.36-49
Abstract

Stem cell-based therapy for type 1 diabetes would benefit from implementation of a cell purification step at the pancreatic endoderm stage. This would increase the safety of the final cell product, allow the establishment of an intermediate-stage stem cell bank, and provide a means for upscaling β cell manufacturing. Comparative gene expression analysis revealed glycoprotein 2 (GP2) as a specific cell surface marker for isolating pancreatic endoderm cells (PECs) from differentiated hESCs and human fetal pancreas. Isolated GP2+ PECs efficiently differentiated into glucose responsive insulin-producing cells in vitro. We found that in vitro PEC proliferation declines due to enhanced expression of the cyclin-dependent kinase... (More)

Stem cell-based therapy for type 1 diabetes would benefit from implementation of a cell purification step at the pancreatic endoderm stage. This would increase the safety of the final cell product, allow the establishment of an intermediate-stage stem cell bank, and provide a means for upscaling β cell manufacturing. Comparative gene expression analysis revealed glycoprotein 2 (GP2) as a specific cell surface marker for isolating pancreatic endoderm cells (PECs) from differentiated hESCs and human fetal pancreas. Isolated GP2+ PECs efficiently differentiated into glucose responsive insulin-producing cells in vitro. We found that in vitro PEC proliferation declines due to enhanced expression of the cyclin-dependent kinase (CDK) inhibitors CDKN1A and CDKN2A. However, we identified a time window when reducing CDKN1A or CDKN2A expression increased proliferation and yield of GP2+ PECs. Altogether, our results contribute tools and concepts toward the isolation and use of PECs as a source for the safe production of hPSC-derived β cells.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
CDKN1A, CDKN2A, cell surface marker, cell-cycle regulators, differentiation, GP2, human embryonic stem cells, insulin-producing beta cells, pancreatic progenitors, type 1 diabetes
in
Cell Reports
volume
19
issue
1
pages
14 pages
publisher
Cell Press
external identifiers
  • scopus:85016930711
  • wos:000398231800004
ISSN
2211-1247
DOI
10.1016/j.celrep.2017.03.032
language
English
LU publication?
yes
id
12ac3ce7-c77e-4d6e-aa1f-867826379b86
date added to LUP
2017-04-27 14:19:24
date last changed
2017-09-18 13:33:29
@article{12ac3ce7-c77e-4d6e-aa1f-867826379b86,
  abstract     = {<p>Stem cell-based therapy for type 1 diabetes would benefit from implementation of a cell purification step at the pancreatic endoderm stage. This would increase the safety of the final cell product, allow the establishment of an intermediate-stage stem cell bank, and provide a means for upscaling β cell manufacturing. Comparative gene expression analysis revealed glycoprotein 2 (GP2) as a specific cell surface marker for isolating pancreatic endoderm cells (PECs) from differentiated hESCs and human fetal pancreas. Isolated GP2<sup>+</sup> PECs efficiently differentiated into glucose responsive insulin-producing cells in vitro. We found that in vitro PEC proliferation declines due to enhanced expression of the cyclin-dependent kinase (CDK) inhibitors CDKN1A and CDKN2A. However, we identified a time window when reducing CDKN1A or CDKN2A expression increased proliferation and yield of GP2<sup>+</sup> PECs. Altogether, our results contribute tools and concepts toward the isolation and use of PECs as a source for the safe production of hPSC-derived β cells.</p>},
  author       = {Ameri, Jacqueline and Borup, Rehannah and Prawiro, Christy and Ramond, Cyrille and Schachter, Karen A. and Scharfmann, Raphael and Semb, Henrik},
  issn         = {2211-1247},
  keyword      = {CDKN1A,CDKN2A,cell surface marker,cell-cycle regulators,differentiation,GP2,human embryonic stem cells,insulin-producing beta cells,pancreatic progenitors,type 1 diabetes},
  language     = {eng},
  month        = {04},
  number       = {1},
  pages        = {36--49},
  publisher    = {Cell Press},
  series       = {Cell Reports},
  title        = {Efficient Generation of Glucose-Responsive Beta Cells from Isolated GP2<sup>+</sup> Human Pancreatic Progenitors},
  url          = {http://dx.doi.org/10.1016/j.celrep.2017.03.032},
  volume       = {19},
  year         = {2017},
}