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The unparalleled breadth of human embryo and induced pluripotent stem cell competence for growth and differentiation is the cornerstone upon which aspirations to use these cells to develop next-generation platforms for discovery and therapy are based. To date, research has predominantly focused on understanding the intrinsic and extrinsic determinants of these competences from the study of development and tissue homeostasis. However, in order to progress this knowledge to the point of actually delivering on the applications in drug discovery and regenerative medicine, commonly promised by academic scientists in the field, it is necessary to improve the efficacy, safety and cost–effectiveness of the systems that currently exist to cultivate them. This begins with the frank acknowledgement that pluripotent stem cells, and all cells that are derived from them, are and will always be artefacts of culture. Thus, although knowledge of mechanisms governing cell lineage specification and behavior in developing and formed tissues is certainly an important foundation upon which to base manipulations – this knowledge can also unnecessarily limit paradigms for how to control the growth and differentiation of pluripotent stem cells ex vivo. This is made clear by the resounding success of genetic and chemical manipulations that can induce a pluripotent cell phenotype in the first place, and corollary achievements in direct cell conversion, which forces a rethink of long-held dogma concerning cell fate hierarchies [1]. The efficacy, safety and cost–effectiveness of any cell culture system hinges on the quality and consistency of the components upon which it is based, which ultimately relies on the extent to which they are biochemically and physically defined, affordably manufactured and available.

The use of donated red blood cells in transfusion is a well-established cellular therapy. However, problems including insufficient supply, transfusion-transmitted infections and the need for immunological matching hamper even in the best services. These issues may be eliminated by using pluripotent stem cells to generate universal donor group O, Rhesus D-negative red blood cells. Human embryonic stem cells can be maintained and expanded indefinitely and can, therefore, produce the very large cell numbers required for this application. Red blood cell production is also an attractive goal for pluripotent stem cell-derived therapeutics because it is a well-characterized single cell suspension, lacking nucleated cells and with a low expression of HLA molecules. Much progress has been made; however, a number of challenges remain including scale-up, clinical effectiveness and product safety.