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Single cell lineage analysis reveals cell fate determination events during directed β-cell differentiation

ABSTRACT: In vitro differentiation of human ES cells into insulin-producing β-like cells offers new opportunities for pancreatic development modeling and potential diabetes therapy. However, the precise molecular events associated with this multi-stage process remain unclear. Here, we generated 95,308 single cell transcriptome data encompassing the entire differentiation process, and reconstructed a tree delineating the fate choices of all major cell populations in both endocrine and non-endocrine lineages. Most detectable genes are dynamically regulated during differentiation, and stage-specific transcription factors create the time-dependent enhancer landscapes. Interestingly, we found that many diabetes/obesity risk genes are only transiently expressed during differentiation. One example is TCF7L2, which peaked during the pancreatic progenitor stages driven by an enhancer located within a diabetes GWAS locus. From the lineage analysis, we found that the NOTCH signaling-downstream gene HES1 is one of the “switch genes” associated with the choice of non-endocrine cell fate; this led to an improved differentiation protocol for better yield of endocrine cells by adjusting the timing of NOTCH inhibition. Additionally, we discovered that ROCKII inhibitor also promotes endocrine differentiation by suppressing non-endocrine lineage. Taken together, our comprehensive single cell lineage analyses provided a valuable resource for the study of pancreatic development and disease etiology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE143783 | GEO | 2020/09/20

REPOSITORIES: GEO

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Project description:deBack2012 - Lineage Specification in Pancreas Development This model of two neighbouring pancreas precursor cells, describes the exocrine versus endocrine lineage specification process. To account for the tissue scale patterns, this couplet model has been extended to hundreds of coupled cells. This model is described in the article: On the role of lateral stabilization during early patterning in the pancreas de Back W., Zhou JX, Brusch L J. R. Soc. Interface 6 February 2013 vol. 10 no. 79 20120766 Abstract: The cell fate decision of multi-potent pancreatic progenitor cells between the exocrine and endocrine lineages is regulated by Notch signalling, mediated by cell–cell interactions. However, canonical models of Notch-mediated lateral inhibition cannot explain the scattered spatial distribution of endocrine cells and the cell-type ratio in the developing pancreas. Based on evidence from acinar-to-islet cell transdifferentiation in vitro, we propose that lateral stabilization, i.e. positive feedback between adjacent progenitor cells, acts in parallel with lateral inhibition to regulate pattern formation in the pancreas. A simple mathematical model of transcriptional regulation and cell–cell interaction reveals the existence of multi-stability of spatial patterns whose simultaneous occurrence causes scattering of endocrine cells in the presence of noise. The scattering pattern allows for control of the endocrine-to-exocrine cell-type ratio by modulation of lateral stabilization strength. These theoretical results suggest a previously unrecognized role for lateral stabilization in lineage specification, spatial patterning and cell-type ratio control in organ development. This model is hosted on BioModels Database and identified by: MODEL1211010000 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Single cell lineage analysis reveals cell fate determination events during directed β-cell differentiation

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