Mesoderm-derived lineages, including the hematopoietic, vascular, and cardiac, are among the easiest to generate from ES cells and have been studied in considerable detail. Of these, hematopoietic development is the best characterized. Findings from several different studies have demonstrated striking parallels between the ES cell model and the early embryo, providing important insights into the embryonic origins of the hematopoietic system. Given these findings, hematopoietic development is covered in the greatest detail in this review.
Following the initial studies demonstrating the presence of hemoglobinized cells in EBs (Doetschman et al. 1985), there was significant interest in modeling various aspects of hematopoietic commitment using the ES cell differentiation model (Burkert et al. 1991; Schmitt et al. 1991; Keller et al. 1993; Nakano et al. 1994). One of the initial goals of many investigators in the field was to generate hematopoietic stem cells (HSCs) from ES cells with the aim of developing a readily accessible supply of transplantable stem cells. HSCs are typically assayed by their ability to provide long-term multilineage hematopoietic repopulation following intravenous (IV) transplantation into hematopoietically deficient animals (Kondo et al. 2003). For a stem cell to function in this assay, it must be multipotent and possess the capacity to home to the bone marrow following transplantation. Despite extensive efforts by many groups during the past 10 years, the development of HSCs from ES cells remains a challenge as most attempts to identify these cells in the differentiation cultures have failed (Muller and Dzierzak 1993; G. Lacaud, V. Kouskoff, M. Kennedy, and G. Keller, unpubl.). These failures prompted a re-evaluation of hematopoietic commitment in the ES cell differentiation cultures from the perspective of hematopoiesis in the early embryo. Patterning hematopoietic development of ES cells in culture on hematopoietic commitment in the early embryo was important as the hematopoietic system undergoes dramatic changes throughout embryonic life (Metcalf and Moore 1971; Russel 1979; Keller et al. 1999). These changes need to be reproduced in the ES cell system if it is to be a valid model of early development and ultimately a source of HSCs.