Pluripotency is defined by the ability of a cell to differentiate to the derivatives of all the three embryonic germ layers: ectoderm, mesoderm and endoderm. Pluripotent cells can be captured via the archetypal derivation of embryonic stem cells or via somatic cell reprogramming. Somatic cells are induced to acquire a pluripotent stem cell (iPSC) state through the forced expression of key transcription factors, and in the mouse these cells can fulfil the strictest of all developmental assays for pluripotent cells by generating completely iPSC-derived embryos and mice. However, it is not known whether there are additional classes of pluripotent cells, or what the spectrum of reprogrammed phenotypes encompasses. Here we explore alternative outcomes of somatic reprogramming by fully characterizing reprogrammed cells independent of preconceived definitions of iPSC states. We demonstrate that by maintaining elevated reprogramming factor expression levels, mouse embryonic fibroblasts go through unique epigenetic modifications to arrive at a stable, Nanog-positive, alternative pluripotent state. In doing so, we prove that the pluripotent spectrum can encompass multiple, unique cell states.
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We are grateful for A. Bang’s expertise and assistance regarding flow cytometry. We thank M. Gertsenstein and M. Pereira for chimaera production, and K. Harpal for teratoma sectioning. We would also like to acknowledge the assistance and support of lab colleagues, collaborators and all the members of the Project Grandiose Consortium who are too numerous to name individually but who made a positive impact on this research. A.N. is Tier 1 Canada Research Chair in Stem Cells and Regeneration. This work was supported by grants awarded to A.N. and I.M.R. from the Ontario Research Fund Global Leadership Round in Genomics and Life Sciences grants (GL2), to A.N. from the Canadian stem cell network (9/5254 (TR3)) and Canadian Institutes of Health Research (CIHR MOP102575), to J.-S.S. by the South Korean Ministry of Knowledge Economy (no. 10037410), SNUCM research fund (grant no. 0411-20100074), and Macrogen Inc. (no. MGR03-11 and 12), to S.G. from the Australian Research Council (no. SR110001002), and to C.A.W. by a Queensland government Smart Futures Fellowship and an ARC by Stem Cells Australia and to T.P. grants from NHMRC and ARC. S.M.I.H. received a fellowship from the McEwen Centre of Regenerative Medicine.
Extended data figures
This file contains Supplementary Information sets 1-6. Supplementary Information 1 contains differentially expressed genes (twotailed Welch t-test p<0.01, FDR<0.01) between 28 transgene-expressing reprogrammed lines and 3 ESC-like lines. Supplementary Information 2 contains differentially expressed genes (Welchs t-test p<0.01 FDR<0.05) between F-class and C-class cells. Supplementary Information 3 contains plurinet genes of statistically significant differential expression between F-class samples and ESC samples. Supplementary Information 4 contains differential gene expression upon inactivation of c-Myc expression in F-class cells. Supplementary Information 5 contains differential gene expression upon treatment of F-class cells with HDAC inhibitors. Supplementary Information 6 contains epigenetic status of loci that exhibited differential gene expression (>5 fold) between F-class state and ESC-like cell state. The status of three epigenetic marks are examined; H3K4 trimethylation (H3K4me3), H3K27 trimethylation (H3K27me3) and CpG methylation. Supplementary Information 7 contains primer sequences for quantitative RT-PCR analysis of gene expression.
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Interrupted reprogramming of alveolar type II cells induces progenitor-like cells that ameliorate pulmonary fibrosis
npj Regenerative Medicine (2018)