The individuality of stem cells

Lander BMC Biology 2011, 9:40 http://www.biomedcentral.com/1741-7007/9/40 CO M M E N T Open Access The individuality of stem cells Arthur D Lander* When a group of immigrants moves into a community in large numbers, so much attention is usually focused on how they are different – in language, customs, appearance, and so on – from everyone else, that little notice is taken of how different they may be from each other. It is only after some time that new immigrant groups tend to be seen as diverse sets of people defined by their individuality, and not merely by their shared group characteristics. Similar things may be said about stem cells. Although not a new subject in biology, in the last decade and a half, stem cells seem truly to have exploded onto the scene of biological research (Figure 1). Not surprisingly, attitudes about stem cells have focused largely on the ways in which they are different from other cells. Thus, basic research on stem cells has been dominated by a search for explanations of properties thought to be common to stem cells, such as self-renewal, immortality, pluripotency and asymmetry of division. Yet in recent years, there has been growing awareness that such properties are not unique to stem cells, nor do all types of stem cells necessarily possess them, nor do those that possess them manifest them at all times. Such recognition that there is diversity and plasticity among types of stem cells has freed us to start paying closer attention to the diversity of behaviors displayed by individual stem cells, even within supposedly homogeneous groups. Percent of publications Year Figure 1. Publications indexed on PubMed by MeSH major topic ‘stem cell’, from 1970 to 2010, as a percentage of total indexed publications. Between 1995 and 2008, the rate of publication on stem cells increased threefold faster than the overall publication rate (which itself nearly doubled over the same period). Do stem cells play dice? Nowhere is such individuality more evident than in clonal-analysis studies, which involve the tracking of stem cells and their offspring over time. Clonal analysis has a long history in the stem-cell field, going back to pioneering work on hematopoietic stem cells in the early 1960s [1]. Such work has always suggested that stem cells behave stochastically – essentially rolling dice at each cell division to determine whether to make two progeny that are both stem cells, two progeny that are non-stem cells, or one of each [2]. Yet for years, most biologists have *Correspondence: adlander@uci.edu 2638 Biological Sciences III, University of California Irvine, Irvine, CA 92697-2300, USA espoused a deterministic view, in which stem cells all behave in predetermined ways, usually dividing asymmetrically (at least under normal circumstances), to produce one stem cell and one ‘transit-amplifying cell’, which then replicates itself a fixed number of times before finally differentiating [3,4]. The widespread adoption by biologists of the deterministic, stem/transit-amplifying model should be seen less as an unwillingness to accept the possibility of stochastic stem-cell behavior than as an expression of hope that the degree of individuality that stem cells display is sufficiently small as to be negligible. Alas, that hope now appears to have been thoroughly dashed by a series of recent studies involving some of the most widely studied tissue stem-cell systems [5-7]. In one case – the mouse small intestine – direct observations indicate that the proportion of times that stem cells divide asymmetrically is astonishingly small, on the order of 20%; the rest of the time they choose equally between making either two stem cells or differentiating [7]. In other cases, such as mouse interfollicular epidermis, asymmetric divisions are more frequent, but still far from exclusive [5]. Rather than having a negligible impact, such behavior should produce highly characteristic and meaningful © 2011 Lander; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.