Similarly, malignancies may represent a special case of stem cell heterogeneity that fits into this broad conceptual framework ( BOX 2). Stem cell systems in other tissues, including stomach, mammary gland and prostate tissues, which are not discussed in this Review, may also be worth reconsidering in light of this evidence 7– 9. Here, we review the evidence in support of such heterogeneity and present instructive examples from haematopoietic, skin and intestinal epithelium that argue in favour of a profound revision of traditional views. However, recent data that were generated using new technologies in various systems ( BOX 1) have indicated that, in many somatic tissues, the stem cell system is surprisingly heterogeneous, comprising different types of stem cells. Traditionally, the stem cell pool within a single tissue was thought to be uniform: all stem cells in the pool were presumed to have equivalent potential for differentiation and self-renewal. Somatic stem cells have thus come to be defined as adult-derived cells that have two hallmark capabilities: the ability to undergo differentiation and generate multiple lineages over long periods of time and the ability to simultaneously self-renew (that is, to regenerate themselves). Data from these experiments reinforced a model in which a single tissue-specific stem cell continuously regenerates some or all of the lineages in a given tissue. As transplantation was not easily practicable in other tissues such as the skin and the intestine, the stem cell paradigm in these tissues gained support through experiments in which cell fates were followed using tritiated thymidine labelling 6. Thus, for more than 50 years, the research field has accepted the view that the haemato poietic system is maintained by a single type of stem cell that regenerates all of the blood lineages during adulthood.Ĭoncepts of tissue regeneration that were developed from the study of haematopoiesis have provided a framework for understanding the mechanisms that underlie the maintenance of other tissues. Corroboration of this idea came from studies in which transplanted cells were marked by retroviral transduction integration sites that were shared by multiple blood lineages were considered to be indicative of a common originating cell 4, 5. In the mid-1950s, bone marrow transplantation in mice, combined with tracking of the cellular progeny of transplanted tissue on the basis of the presence of common chromosomal translocations, strongly supported the hypothesis that cells of both lymphoid and myeloid lineages originate from the same cell 3. For the past century, this concept has been the foundation of our understanding of tissue regeneration. The term ‘stem cell’ ( Stammzelle) first appeared in the literature around 1900, when it was used by Artur Pappenheim and others to promote the common progenitor concept 1 (reviewed in REF. Observations of the bone marrow led to heated debate about whether the distinct lymphoid and myeloid components of the blood were continuously generated from a common cell or from distinct progenitor cells (a view championed by Paul Ehrlich). In the absence of modern experimental tools such as fluorescence imaging, tissue transplantation and animal models, developmental relationships among cell types were inferred from extensive observation of the tissues of interest and documented by detailed hand drawings. In the late 1800s, descriptive pathology portrayed the cellular structure of many organs in exquisite detail.
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