1. Department of Surgery and Cambridge Institute for Medical Research, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0XY, UK
2. CR-UK Viral Oncology Group, Wolfson Institute for Biomedical Research, UCL, Cruciform Building Gower Street, London WC1E 6BT, UK
3. Wellcome Trust/Cancer Research UK Gurdon Institute of Cancer and Developmental Biology and Department of Physiology, University of Cambridge, Tennis Court Road, Cambridge CB2, 1QR, UK
4. Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, University of Cambridge, Cambridge CB2 0XY, UK
5. Medical Genetics Department Cambridge University Hospital NHS Foundation Trust, Kefford House Maris Lane Cambridge CB2 2FF, UK
6. Dept of Laboratory Medicine Clinical Research Centre, Karolinska University Hospital Karolinska Institutet 141 57 Stockholm, Sweden
7. Present address: Hospital for Sick Children, Toronto Medical Discovery Tower 101 College Street, Toronto, Ontario M5G 1L7, TMDT, Canada.

Correspondence to: Ludovic Vallier¹ Correspondence and requests for materials should be addressed to L.V. (Email: lv225@cam.ac.uk).

Abstract

Although the first mouse embryonic stem (ES) cell lines were derived 25 years ago^{1, 2} using feeder-layer-based blastocyst cultures, subsequent efforts to extend the approach to other mammals, including both laboratory and domestic species, have been relatively unsuccessful. The most notable exceptions were the derivation of non-human primate ES cell lines³ followed shortly thereafter by their derivation of human ES cells⁴. Despite the apparent common origin and the similar pluripotency of mouse and human embryonic stem cells, recent studies have revealed that they use different signalling pathways to maintain their pluripotent status. Mouse ES cells depend on leukaemia inhibitory factor and bone morphogenetic protein, whereas their human counterparts rely on activin (INHBA)/nodal (NODAL) and fibroblast growth factor (FGF). Here we show that pluripotent stem cells can be derived from the late epiblast layer of post-implantation mouse and rat embryos using chemically defined, activin-containing culture medium that is sufficient for long-term maintenance of human embryonic stem cells. Our results demonstrate that activin/Nodal signalling has an evolutionarily conserved role in the derivation and the maintenance of pluripotency in these novel stem cells. Epiblast stem cells provide a valuable experimental system for determining whether distinctions between mouse and human embryonic stem cells reflect species differences or diverse temporal origins.

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