Pluripotent stem cells related to embryonic disc exhibit common self-renewal requirements in diverse livestock species

Author:

Kinoshita Masaki1ORCID,Kobayashi Toshihiro23ORCID,Planells Benjamin4,Klisch Doris4,Spindlow Daniel15,Masaki Hideki6,Bornelöv Susanne1,Stirparo Giuliano Giuseppe15ORCID,Matsunari Hitomi7,Uchikura Ayuko7,Lamas-Toranzo Ismael14ORCID,Nichols Jennifer18ORCID,Nakauchi Hiromitsu69ORCID,Nagashima Hiroshi7,Alberio Ramiro4ORCID,Smith Austin15ORCID

Affiliation:

1. Wellcome-MRC Cambridge Stem Cell Institute, Jeffery Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK

2. Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, Okazaki, Aichi 444-8787, Japan

3. Division of Mammalian Embryology, Centre for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan

4. School of Biosciences, University of Nottingham, Sutton Bonington Campus, Nottingham LE12 5RD, UK

5. Living Systems Institute, University of Exeter, Stocker Road, Exeter EX4 4QD, UK

6. Division of Stem Cell Therapy, Distinguished Professor Unit, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan

7. Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, 1-1-1 Higashi-mita, Tama, Kawasaki 214-8571, Japan

8. Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 1GA, UK

9. Institute for Stem Cell Biology and Regenerative Medicine, Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305USA

Abstract

ABSTRACT Despite four decades of effort, robust propagation of pluripotent stem cells from livestock animals remains challenging. The requirements for self-renewal are unclear and the relationship of cultured stem cells to pluripotent cells resident in the embryo uncertain. Here, we avoided using feeder cells or serum factors to provide a defined culture microenvironment. We show that the combination of activin A, fibroblast growth factor and the Wnt inhibitor XAV939 (AFX) supports establishment and continuous expansion of pluripotent stem cell lines from porcine, ovine and bovine embryos. Germ layer differentiation was evident in teratomas and readily induced in vitro. Global transcriptome analyses highlighted commonality in transcription factor expression across the three species, while global comparison with porcine embryo stages showed proximity to bilaminar disc epiblast. Clonal genetic manipulation and gene targeting were exemplified in porcine stem cells. We further demonstrated that genetically modified AFX stem cells gave rise to cloned porcine foetuses by nuclear transfer. In summary, for major livestock mammals, pluripotent stem cells related to the formative embryonic disc are reliably established using a common and defined signalling environment. This article has an associated ‘The people behind the papers’ interview.

Funder

Biotechnology and Biological Sciences Research Council

European Research Council

Medical Research Council

Japan Society for the Promotion of Science

Japan Agency for Medical Research and Development

Wellcome Trust

Publisher

The Company of Biologists

Subject

Developmental Biology,Molecular Biology

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