Abstract
Human embryonic stem cells have unique value for regenerative medicine, as they are capable of differentiating into a broad variety of cell types. Therefore, defining the signalling pathways that control early cell fate decisions of pluripotent stem cells represents a major task. Moreover, modelling the early steps of embryonic development in vitro may provide the best approach to produce cell types with native properties. Here, we analysed the function of key developmental growth factors such as Activin, FGF and BMP in the control of early cell fate decisions of human pluripotent stem cells. This analysis resulted in the development and validation of chemically defined culture conditions for achieving specification of human embryonic stem cells into neuroectoderm, mesendoderm and into extra-embryonic tissues. Importantly, these defined culture conditions are devoid of factors that could obscure analysis of developmental mechanisms or render the resulting tissues incompatible with future clinical applications. Importantly, the growth factor roles defined using these culture conditions similarly drove differentiation of mouse epiblast stem cells derived from post implantation embryos, thereby reinforcing the hypothesis that epiblast stem cells share a common embryonic identity with human pluripotent stem cells. Therefore the defined growth factor conditions described here represent an essential step toward the production of mature cell types from pluripotent stem cells in conditions fully compatible with clinical use ant also provide a general approach for modelling the early steps of mammalian embryonic development.
Highlights
Human Embryonic Stem cells are pluripotent cells cultured from embryos at the blastocyst stage [1]
H9 and hSF-6 Human Embryonic Stem cells (hESCs) lines grown in chemically defined medium (CDM) supplemented with Activin (10 ng/ml) and FGF (12 ng/ml) were plated on plastic dishes pre-coated with human fibronectin [13]
Discussion hESCs and epiblast stem cells (EpiSCs) provide convergent in vitro systems enabling the analysis of mechanisms controlling cell fate decisions during early mammalian development
Summary
Human Embryonic Stem cells (hESCs) are pluripotent cells cultured from embryos at the blastocyst stage [1]. We analysed the effect of key developmental signalling pathways such as Activin/Nodal, FGF and BMP4 on early cell fate decisions of hESCs using an approach based on a fully chemically defined medium This is resulted in the definition of the function of each pathway in the specification of extra-embryonic tissues and the primary germ layers. We developed and validated chemically defined culture conditions for achieving specification of hESCs into neuroectoderm and mesendoderm and into extra-embryonic tissues These culture conditions worked well to promote similar differentiation of epiblast stem cells (EpiSCs) derived from postimplantation mouse embryos [4,5], their effectiveness on mouse Embryonic Stem Cells (mESCs) was limited. These results show that pluripotent mammalian stem cells can be induced
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