Abstract
BackgroundNaïve and primed pluripotent stem cells (PSCs) represent two different pluripotent states. Primed PSCs following in vitro culture exhibit lower developmental potency as evidenced by failure in germline chimera assays, unlike mouse naïve PSCs. However, the molecular mechanisms underlying the lower developmental competency of primed PSCs remain elusive.ResultsWe examine the regulation of telomere maintenance, retrotransposon activity, and genomic stability of primed PSCs and compare them with naïve PSCs. Surprisingly, primed PSCs only minimally maintain telomeres and show fragile telomeres, associated with declined DNA recombination and repair activity, in contrast to naïve PSCs that robustly elongate telomeres. Also, we identify LINE1 family integrant L1Md_T as naïve-specific retrotransposon and ERVK family integrant IAPEz to define primed PSCs, and their transcription is differentially regulated by heterochromatic histones and Dnmt3b. Notably, genomic instability of primed PSCs is increased, in association with aberrant retrotransposon activity.ConclusionsOur data suggest that fragile telomere, retrotransposon-associated genomic instability, and declined DNA recombination repair, together with reduced function of cell cycle and mitochondria, increased apoptosis, and differentiation properties may link to compromised developmental potency of primed PSCs, noticeably distinguishable from naïve PSCs.
Highlights
Naïve and primed pluripotent stem cells (PSCs) represent two different pluripotent states
Conversion of naïve Murine embryonic stem cells (mESCs) to primed mEpiSCs results in repression of DNA recombination repair pathway Naïve mESCs with distal Oct4 GFP fluorescence were maintained in serum/leukemia inhibitory factor (LIF) medium on mitomycin C-inactivated MEFs served as feeder cells
Analysis of cell cycle at P5 showed that cells under primed state displayed extended G1 phase (Additional file 1: Figure S1b), in contrast to naïve mESCs with shorter G1 phase [48, 49]
Summary
Naïve and primed pluripotent stem cells (PSCs) represent two different pluripotent states. Primed PSCs following in vitro culture exhibit lower developmental potency as evidenced by failure in germline chimera assays, unlike mouse naïve PSCs. the molecular mechanisms underlying the lower developmental competency of primed PSCs remain elusive. Murine embryonic stem cells (mESCs) from preimplantation embryos resemble an earlier stage in development known as naïve pluripotent state. Primed epiblast stem cells (mEpiSCs) are derived from murine post-implantation epiblast embryos commonly known to be in primed pluripotent state [1, 2]. Naïve mouse pluripotent stem cells (mPSCs) exhibit germline competence as determined by chimera production test and can generate all-PSC mice by tetraploid embryo complementation (TEC) test, the most stringent functional assay of naïve pluripotency [6,7,8,9]. Naïve and primed pluripotent states exhibit different molecular signatures in the epigenome and transcriptome profile [3, 10, 11, 13,14,15,16,17,18]
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