Unknown,Transcriptomics,Genomics,Proteomics

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Dynamic developmental signaling logic underlying lineage bifurcations during human endoderm induction and patterning from pluripotent stem cells [Endoderm RNA-seq and ChIP-seq data sets]

ABSTRACT: Unraveling complex signaling programs animating developmental lineage-decisions is pivotal to differentiate human pluripotent stem cells (hPSC) into pure populations of desired lineages for regenerative medicine. Developmental signals are strikingly temporally dynamic: BMP and Wnt initially specify primitive streak (progenitor to endoderm) yet 24 hours later suppress endoderm and induce mesoderm. At lineage bifurcations we show mutually-exclusive embryonic lineages are segregated through cross-repressive signals: TGFM-NM-2 and BMP/MAPK duel to respectively specify pancreas versus liver from endoderm. Unilateral endodermal differentiation requires blockade of alternative fates at every stage, revealing a universal developmental strategy for efficient differentiation and anterior-posterior patterning of diverse hPSC lines into highly-pure endodermal populations. This culminated in hPSC-derived hepatic progenitors that, for the first time, engraft long-term in genetically-unconditioned mouse livers and secrete human albumin. Finally, thirty transcriptional and chromatin state maps capturing endoderm commitment revealed endodermal enhancers reside in an unanticipated diversity of "pre-enhancer" chromatin states before activation. Endoderm RNA-seq and ChIP-seq data sets

ORGANISM(S): Homo sapiens

SUBMITTER: Kyle Loh

PROVIDER: E-GEOD-52657 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Efficient endoderm induction from human pluripotent stem cells by logically directing signals controlling lineage bifurcations.

Loh Kyle M KM Ang Lay Teng LT Zhang Jingyao J Kumar Vibhor V Ang Jasmin J Auyeong Jun Qiang JQ Lee Kian Leong KL Choo Siew Hua SH Lim Christina Y Y CY Nichane Massimo M Tan Junru J Noghabi Monireh Soroush MS Azzola Lisa L Ng Elizabeth S ES Durruthy-Durruthy Jens J Sebastiano Vittorio V Poellinger Lorenz L Elefanty Andrew G AG Stanley Edouard G EG Chen Qingfeng Q Prabhakar Shyam S Weissman Irving L IL Lim Bing B

Cell stem cell 20140109 2

Human pluripotent stem cell (hPSC) differentiation typically yields heterogeneous populations. Knowledge of signals controlling embryonic lineage bifurcations could efficiently yield desired cell types through exclusion of alternate fates. Therefore, we revisited signals driving induction and anterior-posterior patterning of definitive endoderm to generate a coherent roadmap for endoderm differentiation. With striking temporal dynamics, BMP and Wnt initially specified anterior primitive streak ( ...[more]

PMID: 24412311

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Project description:We show that high quality microarray gene expression profiles can be obtained following FACS sorting of cells using combinations of transcription factors. We use this transcription factor FACS (tfFACS) methodology to perform a genomic analysis of hESC-derived endodermal lineages marked by combinations of SOX17, GATA4, and CXCR4, and find that triple positive cells have a much stronger definitive endoderm signature than other combinations of these markers. Additionally, SOX17+GATA4+ cells can be obtained at a much earlier stage of differentiation, prior to expression of CXCR4+ cells, providing an important new tool to isolate this earlier definitive endoderm subtype. Overall, tfFACS represents an advancement in FACS technology which broadly crosses multiple disciplines, most notably in regenerative medicine to redefine cellular populations. 21 Total samples were analyzed. Samples collected after 5 days of hESC differentiation included SOX17+GATA4+ CXCR4+ cells, unfixed CXCR4+ cells, and unsorted fixed cells. Samples collected after 3 days of differentiation included SOX17+GATA4+ cells, SOX17-GATA- cells, and unsorted fixed cells. As controls, we analyzed both unfixed hESCs and fixed hESCs. All samples contained biological duplicates, triplicates or quadriplicates. We performed hierarchical clustering to demonstrate whether cellular fixation alone could change gene expression. We based this analysis on 1647 transcript clusters with coefficient of variation > 0.5 across the samples and expression values >= 500 in at least 2 out of the 21 samples. We found that fixation and staining steps did not cause distortions in gene expression measurements. This is supported by the fact that fixed and unfixed cells cluster together based upon differentiation stage, not based upon degree of fixation. Furthermore, using GSEA analysis, we found that the SOX17+GATA4+CXCR4+ day 5 cells and day 3 SOX17+GATA4+ were more enriched for compiled gold-standard endodermal genes than the CXCR4+ day 5 population.