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A XEN-like state bridges somatic cells to pluripotency during chemical reprogramming

ABSTRACT: Pluripotent stem cells can be generated from somatic cells by using pure chemicals.However, the cell fate dynamics and molecular events that occur during the chemical reprogramming process remain unclear. In this study, we found that the chemical reprogramming process requires the early formation of extra-embryonic endoderm (XEN)-like cells and a late transition from XEN-like cells to CiPSCs, a new route that differs from the pathway of transcription factor-induced reprogramming. Moreover, by more precisely manipulating the cell fate transition in a step-wise manner through the XEN-like state, we identified small-molecule boosters and established a robust chemical reprogramming system, with a yield up to 1,000-fold greater than that of the previously reported protocol. These findings demonstrate that chemical reprogramming is a unique and promising approach in the future manipulation of cell fates.

ORGANISM(S): Mus musculus

PROVIDER: GSE73631 | GEO | 2015/12/09

SECONDARY ACCESSION(S): PRJNA297459

REPOSITORIES: GEO

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A XEN-like state bridges somatic cells to pluripotency during chemical reprogramming

Project description:Pluripotent stem cells can be generated from somatic cells by using pure chemicals.However, the cell fate dynamics and molecular events that occur during the chemical reprogramming process remain unclear. In this study, we found that the chemical reprogramming process requires the early formation of extra-embryonic endoderm (XEN)-like cells and a late transition from XEN-like cells to CiPSCs, a new route that differs from the pathway of transcription factor-induced reprogramming. Moreover, by more precisely manipulating the cell fate transition in a step-wise manner through the XEN-like state, we identified small-molecule boosters and established a robust chemical reprogramming system, with a yield up to 1,000-fold greater than that of the previously reported protocol. These findings demonstrate that chemical reprogramming is a unique and promising approach in the future manipulation of cell fates. We analyzed the gene expression profiles of intermediate cells obtained from diferent timepoints during chemical reprogramming process,using RNA-Sequencing. Embryo-derived XEN cells (eXENs), chemically-derived eXEN cell lines (CeXENs), embryonic stem cells (ESCs) and chemically-induced pluripotent stem cells (CiPSCs) are used as controls.

2015-12-09 | E-GEOD-73631 | biostudies-arrayexpress

Chemicals orchestrate reprogramming with hierarchical activation of master transcription factors primed by endogenous Sox17 activation

Project description:Mouse somatic cells can be chemically reprogrammed into pluripotent stem cells (CiPSCs) through an intermediate extraembryonic endoderm (XEN)-like state. However, it is elusive how the chemicals orchestrate the cell fate alteration. In this study, we analyze molecular dynamics in chemical reprogramming from fibroblasts to a XEN-like state. We find that Sox17 is initially activated by the chemical cocktails, and XEN cell fate specialization is subsequently mediated by Sox17 activated expression of other XEN master genes, such as Sall4 and Gata4. Furthermore, this stepwise process is differentially regulated. The core reprogramming chemicals CHIR99021, 616452 and Forskolin are all necessary for Sox17 activation, while differently required for Gata4 and Sall4 expression. The addition of chemical boosters in different phases further improves the generation efficiency of XEN-like cells. Taken together, our work demonstrates that chemical reprogramming is regulated in 3 distinct “prime–specify–transit” phases initiated with endogenous Sox17 activation, providing a new framework to understand cell fate determination.

2020-11-05 | GSE144097 | GEO

Transcriptome-based chemical screens identify CDK8 as a common barrier in multiple cell reprogramming systems [RNA-seq]

Project description:Fibroblasts can be chemically induced to pluripotent stem cells (CiPSCs) through an extraembryonic endoderm (XEN)-like state or directly converted into other differentiated cell lineages. However, the mechanisms underlying chemically-induced cell fate reprogramming remain unclear. Here, a transcriptome-based screen of biologically active compounds uncovered that CDK8 inhibition was essential to enable chemically-induced reprogramming from fibroblasts into XEN-like cells, then CiPSCs. RNA-seq analysis showed that a CDK8 inhibitor, MSC2530818, inhibited pro-inflammatory pathways that suppress chemical reprogramming, and facilitated the induction of a multi-lineage priming state, indicating the establishment of plasticity in fibroblasts. CDK8 inhibition also resulted in chromatin accessibility profile and Pol II occupation profile similar to that under initial chemical reprogramming. Moreover, CDK8 inhibition greatly promoted transgene-mediated reprogramming of mouse fibroblasts into hepatocyte-like cells, and chemical reprogramming of human fibroblasts into adipocytes. These collective findings thus define CDK8 as a general molecular barrier in multiple cell reprogramming processes, and as a common target for inducing plasticity and cell fate conversion.

2023-05-19 | GSE227569 | GEO

Transcriptome-based chemical screens identify CDK8 as a common barrier in multiple cell reprogramming systems [Drug-seq2]

2023-05-19 | GSE227568 | GEO

Transcriptome-based chemical screens identify CDK8 as a common barrier in multiple cell reprogramming systems [ATAC-seq]

2023-05-19 | GSE227566 | GEO

Temporal RNA-seq expression profiling of Sox17-medaited XEN conversion of ESCs

Project description:The transcription factor Sox17 is expressed in early primitive endoderm-fated cells of the mouse embryo and in embryo-derived extraembryonic endoderm (ExEn) stem (XEN) cells. We have shown that overexpression of Sox17 in mouse embryonic stem cells (ESCs) drives cell fate to a committed XEN-like cell state (Sox17-XEN cells). When placed back into the embryo, Sox17-XEN cells contribute exclusively to the ExEn. Transient Sox17 expression is sufficient to drive this fate change during which time cells transit through distinct intermediate states prior to the generation of functional XEN-like cells. We identified dynamic regulatory networks driving Sox17-mediated XEN conversion by analyzing a dynamic regulatory map of gene expression bifurcation points throughout conversion, created using RNA-seq time series data. We found that Sox17 orchestrates this conversion process by acting in autoregulatory and feed-forward network motifs, regulating dynamic gene regulatory networks (GRNs) directing cell fate. We have shown that Sox17-mediated XEN conversion provides a powerful tool for understanding the regulation of cell fate changes and for the elucidation of GRNs regulating lineage decisions in the mouse embryo. Total RNA was extracted during a time course of Sox17 overexpression in mouse ESCs at 7 time points as well as from wild-type ESCs and wild-type XEN cells.

2014-09-05 | E-GEOD-61102 | biostudies-arrayexpress

Lineage Reprogramming of Fibroblasts into Functional Neurons and Hepatocytes via Chemically Induced XEN-like State

Project description:Small-molecule based lineage reprogramming has newly emerged as a promising approach for generating functional cell types. We recently found that the chemical induction of iPSCs from fibroblasts pass through an extra-embryonic endoderm (XEN)-like state. In this study, we demonstrated that these chemically-induced XEN-like cells were not restricted to be reprogrammed to iPSCs, but feasible to be induced into functional neurons, bypassing the pluripotent stage. These induced neurons possessed neuron-specific expression profiles, formed functional synapses in culture dish and further matured after transplantation into brains of adult mice. Notably, by using similar principles, hepatocytes could also be induced from the XEN-like cells. Furthermore, the XEN-like cells are highly expandable (for at least 20 passages), retaining genome stability and lineage specifying potentials. Our study establishes a featured route of chemical lineage reprogramming and may provide a universal platform for generating large amounts of diverse functional cell types via the expandable XEN-like state.

2017-06-28 | GSE97721 | GEO

Temporal RNA-seq expression profiling of Sox17-medaited XEN conversion of ESCs

2014-09-05 | GSE61102 | GEO

Pluripotent Stem Cells Induced from Mouse Neural Stem Cells and Small Intestinal Epithelial Cells by Small Molecule Compounds

Project description:Pluripotent stem cells can be generated by pure small molecule compounds. However, only fibroblasts, a heterogeneous cell population, were reported for use in chemical reprogramming, and the efficiency is relatively low, raising the possibility that chemically induced pluripotent stem cells (CiPSCs) are derived from a specific cell subpopulation residing in fibroblast culture. Thus, it is of interest to know whether chemical reprogramming can be induced in other cell types, even using the same chemical cocktail. Here, using lineage tracing, we verify the generation of CiPSCs from fibroblasts. We further demonstrate that neural stem cells (NSCs) and small intestinal epithelial cells (IECs), cell types from the ectoderm and endoderm, respectively, can be chemically reprogrammed into pluripotent stem cells. CiPSCs derived from NSCs and IECs resemble mouse embryonic stem cells (ESCs) in terms of proliferation rate, global gene expression profiling, epigenetic status, self-renewal and differentiation capacity, and germline transmission competency. Interestingly, in the chemical reprogramming process from different cell types, a pluripotency gene Sall4 was commonly expressed in the initial stage, and the same core small molecules were required, suggesting conservatism underlying chemical reprogramming from different cell types. Moreover, the use of these small molecules should be fine-tuned to meet the requirement of reprogramming from different cell types. Together, these findings demonstrate that our reported chemical reprogramming approach can be reproduced in different cell types and suggest that chemical reprogramming is a promising strategy with the potential to be extended to more initial cell types. We analyzed the gene expression profiles of NSC-derived CiPSCs and IEC-derived CiPSCs ,using RNA-Sequencing. NSCs, IECs, and embryonic stem cells (R1) are controls.

2016-07-03 | E-GEOD-75522 | biostudies-arrayexpress

Highly efficient and rapid generation of human pluripotent stem cells by chemical reprogramming (RNA-Seq)

Project description:We recently demonstrated the chemical reprogramming of human somatic cells to pluripotent stem cells, which provides a fundamentally new approach for cell fate manipulation. However, the utility of this chemical approach is currently hampered by the slow kinetics. Here, by screening for new small-molecule boosters and systematically optimizing the original chemical reprogramming condition, we have established a robust, chemically defined protocol. With this new protocol, the entire chemical reprogramming process is remarkably accelerated, reducing the time needed from ~50 days to a minimum of 16 days. Moreover, this new protocol enables highly reproducible and efficient generation of human pluripotent stem cells from all 17 tested donors with a reprogramming efficiency of up to 31%. Our method provides a unique and powerful strategy for human cell fate manipulation and pluripotent stem cell manufacturing for cell-based therapeutic applications.

2023-04-26 | GSE213161 | GEO

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