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Glycoprotein 2 is a specific cell surface marker of human pancreatic progenitors.

ABSTRACT: PDX1+/NKX6-1+ pancreatic progenitors (PPs) give rise to endocrine cells both in vitro and in vivo. This cell population can be successfully differentiated from human pluripotent stem cells (hPSCs) and hold the potential to generate an unlimited supply of ? cells for diabetes treatment. However, the efficiency of PP generation in vitro is highly variable, negatively impacting reproducibility and validation of in vitro and in vivo studies, and consequently, translation to the clinic. Here, we report the use of a proteomics approach to phenotypically characterize hPSC-derived PPs and distinguish these cells from non-PP populations during differentiation. Our analysis identifies the pancreatic secretory granule membrane major glycoprotein 2 (GP2) as a PP-specific cell surface marker. Remarkably, GP2 is co-expressed with NKX6-1 and PTF1A in human developing pancreata, indicating that it marks the multipotent pancreatic progenitors in vivo. Finally, we show that isolated hPSC-derived GP2+ cells generate ?-like cells (C-PEPTIDE+/NKX6-1+) more efficiently compared to GP2- and unsorted populations, underlining the potential therapeutic applications of GP2.Pancreatic progenitors (PPs) can be derived from human pluripotent stem cells in vitro but efficiency of differentiation varies, making it hard to sort for insulin-producing cells. Here, the authors use a proteomic approach to identify the secretory granule membrane glycoprotein 2 as a marker for PDX1+/NKX6-1+ PPs.

SUBMITTER: Cogger KF

PROVIDER: S-EPMC5569081 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Glycoprotein 2 is a specific cell surface marker of human pancreatic progenitors.

Cogger Kathryn F KF Sinha Ankit A Sarangi Farida F McGaugh Emily C EC Saunders Diane D Dorrell Craig C Mejia-Guerrero Salvador S Aghazadeh Yasaman Y Rourke Jillian L JL Screaton Robert A RA Grompe Markus M Streeter Philip R PR Powers Alvin C AC Brissova Marcela M Kislinger Thomas T Nostro M Cristina MC

Nature communications 20170824 1

PDX1<sup>+</sup>/NKX6-1<sup>+</sup> pancreatic progenitors (PPs) give rise to endocrine cells both in vitro and in vivo. This cell population can be successfully differentiated from human pluripotent stem cells (hPSCs) and hold the potential to generate an unlimited supply of β cells for diabetes treatment. However, the efficiency of PP generation in vitro is highly variable, negatively impacting reproducibility and validation of in vitro and in vivo studies, and consequently, translation to the ...[more]

PMID: 28835709

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Project description:BACKGROUND:The development of novel targeted cancer therapies and/or diagnostic tools is dependent upon an understanding of the differential expression of molecular targets between normal tissues and tumors. Many of these potential targets are cell-surface receptors; however, our knowledge of the cell-surface proteins upregulated in pancreatic tumors is limited, thus impeding the development of targeted therapies for pancreatic cancer. To develop new diagnostic and therapeutic tools to specifically target pancreatic tumors, we sought to identify cell-surface proteins that may serve as potential tumor-specfic targets. METHODS:Membrane glycoproteins on the pancreatic cancer cell lines BxPC-3 were labeled with the bifunctional linker biocytin hydrazide. Following proteolytic digestion, biotinylated glycopeptides were captured with streptavidin-coupled beads then released by PNGaseF-mediated endoglycosidase cleavage and identified by liquid chromatography-tandem mass spectrometry (MS). A protein identified by the cell-surface glycoprotein capture procedure, CD109, was evaluated by western analysis of lysates of pancreatic cancer cell lines and by immunohistochemistry in sections of pancreatic ductal adenocarcinoma and non- neoplastic pancreatic tissues. RESULTS:MS/MS analysis of glycopeptides captured from BxPC-3 cells revealed 18 proteins predicted or known to be associated with the plasma membrane, including CD109, which has not been reported in pancreatic cancer. Western analysis of CD109 in lysates prepared from pancreatic cancer cell lines revealed it was expressed in 6 of 8 cell lines, with a high level of expression in BxPC-3, MIAPaCa-2, and Panc-1 cells. Immunohistochemical analyses of human pancreatic tissues indicate CD109 is significantly overexpressed in pancreatic tumors compared to normal pancreas. CONCLUSIONS:The selective capture of glycopeptides from the surface of pancreatic cancer cell lines can reveal novel cell-surface glycoproteins expressed in pancreatic ductal adenocarcinomas.

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Glycoprotein 2 is a specific cell surface marker of human pancreatic progenitors.

Publications

Glycoprotein 2 is a specific cell surface marker of human pancreatic progenitors.

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