The concept of hematopoietic stem cells More than a

The concept of hematopoietic stem cells: More than a century ago The development of cell biology research coincides with the advance of microscopes in the 19th century. It was finally possible to directly observe the various blood cell types and to witness their proliferation and differentiation (Mazzarello, 1999). On the basis of his observations, the German pathologist Franz Ernst Christian Neumann (1834–1918) concluded that the site of blood formation was the bone marrow. He also proposed the pioneer theory in which one cell might be at the origin of all blood cell lineages. The Russian scientist Alexander A. Maximow (1874–1928) also developed and introduced the theory of a common cell for the complete blood-building system or hematopoiesis, as well as the idea of a micro-environmental niche for these TIC10 manufacturer within the bone marrow (Maximow, 1909). The concept of Hematopoietic Stem Cells (HSCs), although very controversial at the time, was born and has led to the beginning of stem cell research (Ramalho-Santos and Willenbring, 2007). Ernest A. McCulloch and James E. Till gave the first experimental proof of the stem cell theory by performing the transplantation of bone marrow cells into irradiated mice (Till and McCulloch, 1961; Becker et al., 1963). These cells gave rise to myeloid multilineage colonies in the spleen of transplanted animals, the number of colonies being proportional to the number of injected cells. Such experiments demonstrated the multilineage potential of single bone marrow cells (so-called CFU-S, Colony-Forming Unit in the Spleen) (Siminovitch et al., 1963). However, because these cells only have limited self-renewing capabilities, they are not considered to be true stem cells which must be both multipotent and self-renewing. E. Donnall Thomas performed the first successful stem cell transplantation on identical human twins in 1957 (Thomas et al., 1957). This has formally demonstrated that intravenous injection of bone marrow cells allows long-term repopulation with the production of new blood cells. The oncologist Georges Mathé also performed transplantations on Yugoslavian nuclear workers whose bone marrows were damaged by irradiation (Mathé et al., 1959). Later on, he successfully cured a patient with leukemia (pre-treated by irradiation) after allogenic bone marrow transplantation (Mathé et al., 1963). For nearly 50years, such transplantations have been performed to treat patients with blood-related disorders. Adult HSCs can now be highly enriched with a combination of several surface markers. However, no unique HSC marker has so far been identified, as is the case for most stem cell categories. Thus, a functional test is required to prove that genuine HSCs are present in a cell population. In vivo transplantation is the gold standard experimental procedure to prove retrospectively, by analyzing the HSC progeny, that the cells are capable of multilineage differentiation in addition to self-renewal. Adult bone marrow, cord blood and mobilized peripheral blood are sources of HSCs used in transplantation protocols in the case of many blood-related diseases, such as leukemia. However, the number of HSCs in these tissues remains low, which creates a major obstacle for both HSC use in clinical and fundamental research. Despite extensive studies and a continuously better understanding of the complicated intrinsic and extrinsic regulation of HSCs, it is still very difficult to reproduce in vitro conditions allowing efficient HSC expansion without inducing cell differentiation (Hofmeister et al., 2007). Embryonic Stem Cells (ESC) and induced Pluripotent Stem (iPS) cells can generate in vitro cells of the different hematopoietic lineages including erythrocytes, myelocytes and megakaryocytes (Sakamoto et al., 2010). However, the generation of new HSCs either from ESCs or iPS cells, although very promising, remains very limited to date (Kyba et al., 2002; Burt et al., 2004). Interestingly, it was recently shown that human fibroblasts derived from the skin could directly be reprogrammed to multilineage hematopoietic progenitors after ectopic expression of the single transcription factor Oct-4 (Szabo et al., 2010). Reprogrammation without the need to generate artificial pluripotent stem cells might be a promising direction in the future to generate HSCs in vitro.