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Derivation of stable embryonic stem cell-like, but transcriptionally heterogenous, induced pluripotent stem cells from non-permissive mouse strains

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Abstract

Genetic background is known to play a role in the ability to derive pluripotent, embryonic stem cells (ESC), a trait referred to as permissiveness. Previously we demonstrated that induced pluripotent stem cells (iPSC) can be readily derived from non-permissive mouse strains by addition of serum-based media supplemented with GSK3B and MEK inhibitors, termed 2iS media, 3 days into reprogramming. Here, we describe the derivation of second type of iPSC colony from non-permissive mouse strains that can be stably maintained independently of 2iS media. The resulting cells display transcriptional heterogeneity similar to that observed in ESC from permissive genetic backgrounds derived in conventional serum containing media supplemented with leukemia inhibitor factor. However, unlike previous studies that report exclusive subpopulations, we observe both exclusive and simultaneous expression of naive and primed cell surface markers. Herein, we explore shifts in pluripotency in the presence of 2iS and characterize heterogenous subpopulations to determine their pluripotent state and role in heterogenous iPSCs derived from the non-permissive NOD/ShiLtJ strain. We conclude that heterogeneity is a naturally occurring, necessary quality of stem cells that allows for the maintenance of pluripotency. This study further demonstrates the efficacy of the 2iS reprogramming technique. It is also the first study to derive stable ESC-like stem cells from the non-permissive NOD/ShiLtJ and WSB/EiJ strains, enabling easier and broader research possibilities into pluripotency for these and similar non-permissive mouse strains and species.

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source population. There is less variance between PECAM1+ cells and dual expressing cells than between either and CD40+ cells. b There are fewer differentially expressed genes between PECAM1+ cells and the ESC state than PECAM1+ cells and the EpiSC state. The same is true for flow-sorted dual expressing cells. However, CD40+ cells are equally dissimilar to both the ESC state and the EpiSC state as judged by a roughly equal number of differentially expressed genes in each comparison. c1–4 Culture of PECAM1+ cells flow sorted cells separately yields a re-emergence of all three subpopulations. c1–2 Single channel images of each marker. c3 Merged image of both markers. c1–3 Scale bar 200 µm. c4 Enlarged region of c3 panel, scale bar 30 µm. d1–4 Culture of CD40+ flow sorted cells separately yields a re-emergence of all three subpopulations. These images are representative of the population 3 to 4 days after separate growth. The cells have not been passaged

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Acknowledgements

We would like to thank Jacob Hanna (Weizmann Institute of Science) for the NOD/ShiLtJ ESC, Ludovic Vallier (Welcome Sanger Institute) for the NOD/ShiLtJ EpiSC, Laura Reinholdt (The Jackson Laboratory) for the NOD/ShiLtJ, WSB/EiJ, and 129S1/SvImJ ESC, and Alice Jouneau (French National Institute for Agricultural Research) for the 129 EpiSC.

Funding

This work was supported by National Institutes of Health Grants P50 MH090338 and RM1 HG008529 to DWT and U01 ES026717 to DLA, and a National Science Foundation Graduate Fellowship to TG.

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Authors and Affiliations

  1. Program in Genetics, Department of Biological Science, North Carolina State University, Raleigh, NC, 27695, USA

    Tiffany A. Garbutt, Thomas Konneker, Drake Phelps, Alexis Jones & David Aylor

  2. Texas A&M Institute for Genome Sciences and Society, Texas A&M University, College Station, TX, 77843, USA

    Kranti Konganti, Andrew Hillhouse & David W. Threadgill

  3. Department of Molecular and Cellular Medicine, Texas A&M University, College Station, TX, 77843, USA

    Kranti Konganti, Andrew Hillhouse & David W. Threadgill

  4. Department of Biochemistry & Biophysics, Texas A&M University, College Station, TX, 77843, USA

    David W. Threadgill

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  1. Tiffany A. Garbutt
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Correspondence to David W. Threadgill.

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Garbutt, T.A., Konganti, K., Konneker, T. et al. Derivation of stable embryonic stem cell-like, but transcriptionally heterogenous, induced pluripotent stem cells from non-permissive mouse strains. Mamm Genome 31, 263–286 (2020). https://doi.org/10.1007/s00335-020-09849-x

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