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

Cogger, Kathryn; Sinha, Ankit; Sarangi, Farida; McGaugh, Emily C.; Saunders, Diane; Dorrell, Craig; Mejia-Guerrero, Salvador; Aghazadeh, Yasaman; Rourke, Jillian L.; Screaton, Robert A.; Grompe, Markus; Streeter, Philip R.; Powers, Alvin C.; Briššová, Marcela; Kislinger, Thomas; Nostro, M. Cristina

doi:10.1038/s41467-017-00561-0

Cited by 131 publications

(148 citation statements)

References 35 publications

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“…TSPAN8 is expressed in the gastrointestinal tract and several carcinomas (Agaësse et al, 2017;Zhu et al, 2017;Zhao et al, 2018) and GP2 is expressed in the pancreas and gastrointestinal tract (Cogger et al, 2017;Ohno & Hase, 2010); loss of tolerance to GP2 is associated with Crohn's disease and primary sclerosing cholangitis (Werner et al, 2013;Tornai et al, 2018). Expression of both TRAs is enhanced in mTEC by the presence of AIRE and can be detected on their cell surface by flow cytometry.…”

Section: Large Scale Single-cell Rna-sequencing Data From Facs Sortedmentioning

confidence: 99%

Biologically indeterminate yet ordered promiscuous gene expression in single medullary thymic epithelial cells

Dhalla

Baran-Gale

Maio

et al. 2019

Preprint

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During thymic negative selection, medullary thymic epithelial cells (mTEC) collectively express most protein coding genes, a process termed promiscuous gene expression (PGE). Although PGE is crucial for inducing central T-cell tolerance, this process has not been established definitively as being either stochastic or coordinated. To resolve this question, we sequenced the transcriptomes of 6,894 single mTEC, including 1,795 rare cells expressing either of two tissue-restricted antigens, TSPAN8 or GP2. Transcriptional heterogeneity allowed partitioning of mTEC into 15 robustly-defined subpopulations representing distinct maturational stages and subtypes. Although 50 gene co-expression groups were robustly identified, few could be explained by chromosomal location, biological pathway, or tissue specificity. Further, GP2+ mTEC were randomly dispersed spatially within medullary islands. Thus although PGE exhibits ordered co-expression, biologically it is indeterminate. This likely enhances the presentation of diverse antigens to passing thymocytes during their medullary residency, while simultaneously maintaining mTEC identity throughout PGE.

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Section: Large Scale Single-cell Rna-sequencing Data From Facs Sortedmentioning

confidence: 99%

Biologically indeterminate yet ordered promiscuous gene expression in single medullary thymic epithelial cells

Dhalla

Baran-Gale

Maio

et al. 2019

Preprint

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“…Importantly, studies on hMPCs have been hindered by scarce accessibility to fetal tissues and few isolation methods that allow for recovery of live cells. To isolate MPCs, most laboratories rely on the use of fluorescent reporter proteins in transgenic animal models or cell‐surface markers obtained by screening of in vitro‐derived hMPC‐like cells . We recently reported the successful isolation of live renal progenitor cells from human fetal kidney using RNA‐based fluorescent probes (Smartflare technology) combined with fluorescence‐activated cell sorting (FACS) .…”

Section: Introductionmentioning

confidence: 99%

SOX9+/PTF1A+ Cells Define the Tip Progenitor Cells of the Human Fetal Pancreas of the Second Trimester

Villani

Thornton

Zook

et al. 2019

Stem Cells Translational Medicine

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Significant progress has been made in recent years in characterizing human multipotent progenitor cells (hMPCs) of the early pancreas; however, the identity and persistence of these cells during the second trimester, after the initiation of branching morphogenesis, remain elusive. Additionally, studies on hMPCs have been hindered by few isolation methods that allow for the recovery of live cells. Here, we investigated the tip progenitor domain in the branched epithelium of human fetal pancreas between 13.5 and 17.5 gestational weeks by immunohistological staining. We also used a novel RNA-based technology to isolate live cells followed by gene expression analyses. We identified cells co-expressing SOX9 and PTF1A, two transcription factors known to be important for pancreatic MPCs, within the tips of the epithelium and observed a decrease in their proportions over time. Pancreatic SOX9+/PTF1A+ cells were enriched for MPC markers, including MYC and GATA6. These cells were proliferative and appeared active in branching morphogenesis and matrix remodeling, as evidenced by gene set enrichment analysis. We identified a hub of genes pertaining to the expanding tip progenitor niche, such as FOXF1, GLI3, TBX3, FGFR1, TGFBR2, ITGAV, ITGA2, and ITGB3. YAP1 of the Hippo pathway emerged as a highly enriched component within the SOX9+/PTF1A+ cells. Single-cell RNA-sequencing further corroborated the findings by identifying a cluster of SOX9+/PTF1A+ cells with multipotent characteristics. Based on these results, we propose that the SOX9+/PTF1A+ cells in the human pancreas are uncommitted MPC-like cells that reside at the tips of the expanding pancreatic epithelium, directing self-renewal and inducing pancreatic organogenesis. STEM CELLS TRANSLATIONAL MEDICINE 2019;8:1249-1264 SIGNIFICANCE STATEMENTWith the use of RNA-labeling probes, the authors report for the first time the direct isolation of live pancreatic progenitors co-expressing SOX9 and PTF1A from human pancreas of the second trimester. Pancreatic multipotent progenitor state was confirmed by gene profiling by bulk RNA-seq and single cell RNA-seq. This first "snapshot" of the transcriptional network of human pancreatic progenitors opens new avenues in understanding human pancreas development, pancreatic specification and supports the ultimate goal of understanding possible mechanisms for pancreas regeneration.

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“…Fig. 2), which has been shown to enrich for endocrine progenitors [24], [25]. Levels of acetylated lysine were not significantly reduced in GP2+ cells compared to GP2-cells, indicating similar levels of sirtuin activity in both populations (Fig.…”

Section: Resultsmentioning

confidence: 79%

Nicotinamide promotes differentiation of pancreatic endocrine progenitors from human pluripotent stem cells through poly (ADP-ribose) polymerase inhibition

Woodford

Yin

Chang

et al. 2020

Preprint

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The generation of pancreatic endocrine progenitor cells is an important step in the differentiation of beta cells from human pluripotent stem cells (hPSC). This stage is marked by the expression of Nkx6.1, a transcription factor with well understood downstream targets but with unclear upstream regulators. In hPSC differentiation, Nkx6.1 is strongly induced by nicotinamide, a derivative of vitamin B3, which has three known functions within a cell. Nicotinamide inhibits two classes of enzymes known as poly-ADP-ribose polymerases (PARPs) and sirtuins. It also contributes to the cellular pool of nicotinamide adenosine deoxynucleotide (NAD+) after conversion in the nicotinamide salvage pathway. Induction of Nkx6.1 expression in pancreatic endocrine progenitors by nicotinamide was mimicked by 3 PARP inhibitors (PJ34, olaparib, NU1025). Small molecule inhibition of the nicotinamide salvage pathway reduced Nkx6.1 expression but not Pdx1 expression and caused alteration in NAD+/NADH ratio. Nkx6.1 expression was not affected by sirtuin inhibition. Metabolic profiling of differentiating pancreatic and endocrine progenitors showed that oxygen consumption increases as differentiation progresses, and that nicotinamide reduces oxygen consumption rate. Expression of Nkx6.1 and other beta cell related genes, including Ins2 and Pdx1 increased in mouse islets after exposure to nicotinamide. In summary, nicotinamide induced Nkx6.1 expression in differentiating human pancreatic endocrine progenitors through inhibition of the PARP family of enzymes. Nicotinamide administration was also associated with increased NAD+/NADH ratio, without affecting Nkx6.1 expression. Similarly, the association between nicotinamide and Nkx6.1 expression was also seen in isolated mouse islets. These observations show a link between the regulation of beta cell identity and the effectors of NAD+ metabolism, suggesting possible therapeutic targets in the field of diabetes.

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

Cited by 131 publications

References 35 publications

Biologically indeterminate yet ordered promiscuous gene expression in single medullary thymic epithelial cells

Biologically indeterminate yet ordered promiscuous gene expression in single medullary thymic epithelial cells

SOX9+/PTF1A+ Cells Define the Tip Progenitor Cells of the Human Fetal Pancreas of the Second Trimester

Nicotinamide promotes differentiation of pancreatic endocrine progenitors from human pluripotent stem cells through poly (ADP-ribose) polymerase inhibition

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