Abstract
Mouse embryonic stem (ES) cells are defined by their capacity to self-renew and their ability to differentiate into all adult tissues including the germ line. Along with efficient clonal propagation, these properties have made them an unparalleled tool for manipulation of the mouse genome. Traditionally, mouse ES (mES) cells have been isolated and cultured in complex, poorly defined conditions that only permit efficient derivation from the 129 mouse strain; genuine ES cells have not been isolated from another species in these conditions. Recently, use of small molecule inhibitors of glycogen synthase kinase 3 (Gsk3) and the Fgf-MAPK signaling cascade has permitted efficient derivation of ES cells from all tested mouse strains. Subsequently, the first verified ES cells were established from a non-mouse species, Rattus norvegicus. Here, we summarize the advances in our understanding of the signaling pathways regulating mES cell self-renewal that led to the first derivation of rat ES cells and highlight the new opportunities presented for transgenic modeling on diverse genetic backgrounds. We also comment on the implications of this work for our understanding of pluripotent stem cells across mammalian species.
Highlights
Embryonic stem (ES) cells were first isolated in 1981 by Martin in California [1] and Evans and Kaufman in Cambridge [2]
The development of homologous recombination technology in cultured mammalian cells and its application to mouse ES cells made possible extensive targeted manipulation of the mouse genome; the engineered cell lines and the mice derived from them have revolutionized our ability to study the effects of gene function in mammalian biology and disease [5]
Only the 129 strain from which ES cells were originally isolated proved consistently amenable to ES cell derivation and genetic manipulation
Summary
Embryonic stem (ES) cells were first isolated in 1981 by Martin in California [1] and Evans and Kaufman in Cambridge [2]. It has been demonstrated that mES cells can be derived and maintained using small molecule inhibitors of Gsk and the Fgf-MAPK signaling cascade (CHIRON99021 and PD0325901, respectively) [24] This two-inhibitor (2i) culture condition has facilitated the derivation of ES cells from all tested mouse strains [24,25] and several strains of a second species, Rattus norvegicus [26,27,28,29]. Genetic or pharmacological inhibition of the Fgf-MAPK pathway blocks efficient ES cell differentiation [36,37,38,39] This finding indicates that shielding ES cells from the inductive signals in their environment is an important aspect for their maintenance in vitro. This optimized condition, 2i+LIF, has since been used to derive ES cells from previously recalcitrant strains and species
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