Sequential progenitor states mark the generation of pancreatic endocrine lineages in mice and humans

Yu, Xinxin; Qiu, Wei-Lin; Liu, Yang; Wang, Yanchun; He, Mao‐Yang; Wang, Dan; Zhang, Yu; Li, Lin‐Chen; Zhang, Jing; Wang, Yi; Xu, Cheng‐Ran

doi:10.1038/s41422-021-00486-w

Cited by 35 publications

(52 citation statements)

References 76 publications

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“…Our single-cell RNA sequencing dataset indicated that human pancreatic cells undergo a gradual differentiation process after NEUROG3 initiation. The similarity between in vitro and in vivo gene expression profiles indicates that the downstream transcriptional program after NEUROG3 expression is robust and can be captured faithfully in human in vitro pancreatic differentiation systems (Yu et al, 2021). This finding extends previous observations as the convergence of the transcriptional program during endocrine induction was also reported in less extensive qPCR-based single-cell profiling of in vivo and in vitro-derived pancreatic cells (Ramond et al, 2018).…”

Section: Initial Steps After Neurog3 Induction Are Similar In Vitro and In Vivo And Neurog3+ Cells From Human Fetal Pancreata Can Also DIsupporting

confidence: 83%

“…Even though validating our results in vivo is not trivial, we compared some of our findings to the recent study by Yu et al, where different populations from human fetal pancreata spanning from 9 to 19 weeks post conception were sequenced using a deep single-cell RNA sequencing method (Yu et al, 2021). We found similar transcriptional signatures of EP1, EP2, and EP3 clusters to the reported human fetal pancreas-derived endocrine progenitor clusters (Table 1).…”

Section: Neurog3+ Human Pancreatic Cells Behave Similarly In 2d and 3d Culturing Conditionssupporting

confidence: 81%

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A combined transcriptional and dynamic roadmap of single human pancreatic endocrine progenitors reveals proliferative capacity and differentiation continuum

Beydag-Tasöz

D’Costa

Hersemann

et al. 2021

Preprint

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SummaryBasic helix-loop-helix genes, particularly proneural genes, are well-described triggers of cell differentiation, yet limited information exists on their dynamics, notably in human development. Here, we focus on Neurogenin 3 (NEUROG3), which is crucial for pancreatic endocrine lineage initiation. Using a double reporter to monitor endogenous NEUROG3 transcription and protein expression in single cells in 2D and 3D models of human pancreas development, we show peaks of expression for the RNA and protein at 22 and 11 hours respectively, approximately two-fold slower than in mice, and remarkable heterogeneity in peak expression levels all triggering differentiation. We also reveal that some human endocrine progenitors proliferate once, mainly at the onset of differentiation, rather than forming a subpopulation with sustained proliferation. Using reporter index-sorted single-cell RNA-seq data, we statistically map transcriptome to dynamic behaviors of cells in live imaging and uncover transcriptional states associated with variations in motility as NEUROG3 levels change, a method applicable to other contexts.

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Section: Initial Steps After Neurog3 Induction Are Similar In Vitro and In Vivo And Neurog3+ Cells From Human Fetal Pancreata Can Also DIsupporting

confidence: 83%

Section: Neurog3+ Human Pancreatic Cells Behave Similarly In 2d and 3d Culturing Conditionssupporting

confidence: 81%

A combined transcriptional and dynamic roadmap of single human pancreatic endocrine progenitors reveals proliferative capacity and differentiation continuum

Beydag-Tasöz

D’Costa

Hersemann

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…The more accurate the estimation of the changing expression levels of genes are, the more reliable CITL will be. Despite the two obstacles, RNA velocity has proved its usefulness in estimating the transcriptional changes of genes in many applications [ 20 , 21 , 22 ]. Our simulations with multiple combinations of the variances and asynchronous regulations show the robustness of CITL.…”

Section: Discussionmentioning

confidence: 99%

Inferring Time-Lagged Causality Using the Derivative of Single-Cell Expression

Wei

Lü

Zhao

2022

IJMS

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Many computational methods have been developed to infer causality among genes using cross-sectional gene expression data, such as single-cell RNA sequencing (scRNA-seq) data. However, due to the limitations of scRNA-seq technologies, time-lagged causal relationships may be missed by existing methods. In this work, we propose a method, called causal inference with time-lagged information (CITL), to infer time-lagged causal relationships from scRNA-seq data by assessing the conditional independence between the changing and current expression levels of genes. CITL estimates the changing expression levels of genes by “RNA velocity”. We demonstrate the accuracy and stability of CITL for inferring time-lagged causality on simulation data against other leading approaches. We have applied CITL to real scRNA data and inferred 878 pairs of time-lagged causal relationships. Furthermore, we showed that the number of regulatory relationships identified by CITL was significantly more than that expected by chance. We provide an R package and a command-line tool of CITL for different usage scenarios.

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“…Although the correlation between PP cells and GHS-R1a has not been fully discussed for a long time, two recent publications have investigated such a correlation. After performing a comprehensive gene expression analysis using human and rodent islets, Yu and colleagues detected GHS-R1 gene expression in PP cells 27 . Furthermore, Gupta and colleague elucidated that GHS-R1a was expressed on most PP and δ cells in human and mouse islets 28 .…”

Section: Discussionmentioning

confidence: 99%

Therapeutic effects of acylated ghrelin-specific receptor GHS-R1a antagonist in islet transplantation

Chinen

Sakata

Yoshimatsu

et al. 2021

Sci Rep

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Islet transplantation is a type of cellular replacement therapy for severe diabetes that is limited by compromising effect on engrafted islets. Trials aiming to improve the function of transplanted islets have also been challenging. This study attempted to elucidate whether regulation of growth hormone secretagogue receptor-1a (GHS-R1a), one of the ghrelin receptors, improve the therapeutic effects of islet transplantation using [D-Lys3]-GHRP-6 (DLS), a specific GHS-R1a antagonist. The therapeutic effects of DLS were assessed in terms of the expression/production of endocrine genes/proteins, insulin-releasing function under glucose stimulation of mouse islets, and outcomes of syngeneic murine islet transplantation with systemic DLS administration. DLS treatment promoted insulin production and suppressed somatostatin production, suggesting that cancelation of the binding between ghrelin and GHS-R1a on β or δ cells improved insulin expression. DLS also promoted the glucose-dependent insulin-releasing function of β cells. However, the therapeutic effect of DLS in islet transplantation was fractional. In conclusion, the GHS-R1a antagonist showed preferable effects in improving the therapeutic outcomes of islet transplantation, including the promotion of insulin-releasing function.

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Sequential progenitor states mark the generation of pancreatic endocrine lineages in mice and humans

Cited by 35 publications

References 76 publications

A combined transcriptional and dynamic roadmap of single human pancreatic endocrine progenitors reveals proliferative capacity and differentiation continuum

A combined transcriptional and dynamic roadmap of single human pancreatic endocrine progenitors reveals proliferative capacity and differentiation continuum

Inferring Time-Lagged Causality Using the Derivative of Single-Cell Expression

Therapeutic effects of acylated ghrelin-specific receptor GHS-R1a antagonist in islet transplantation

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