Two distinct types of cell division have been observed during the development of both invertebrates and vertebrates: symmetrical and asymmetrical cell divisions. An asymmetric cell division produces two daughter cells with different properties. This is in contrast to symmetric cell divisions, which give rise to equivalent daughter cells. Notably, stem cells divide asymmetrically to give rise to two distinct daughter cells: one copy of themselves and one cell programmed to differentiate into another cell type.
asymmetric
Animals are made up of a vast number of distinct cell types. During development, these cell types are generated from a single cell, the zygote. Asymmetric divisions contribute to this expansion in cell type diversity by making two types of cells from one. For example, it is thought that many of the cells in the central nervous system derive from asymmetric divisions. Cells may divide asymmetrically to produce two novel cells at the expense of the mother cell. For example, in plants, an asymmetric division of an unspecialized epidermal cell can produce a guard cell mother cell that divides again to produce two guard cells—the cells that control the closing and opening of stomata.
In principle, there are two mechanisms by which distinct properties may be conferred on the daughters of a dividing cell. In one, the daughter cells are initially equivalent, but a difference is induced by signaling between the cells. In another, the prospective daughter cells are made different at the time of division of the mother cell. Because this latter mechanism does not depend on the interactions of the cells with their environment, it must rely on intrinsic asymmetry. The term asymmetric cell division usually refers to such intrinsic asymmetric divisions. Intrinsic asymmetric divisions rely on the following mechanism: At mitosis, certain proteins are localized asymmetrically to one half of the cell. Next, the cell is cleaved to separate the two halves. Thus, the asymmetrically localized proteins are inherited to only one of the daughter cells, causing that cell to be different from its sibling. Because these proteins determine what becomes of a cell, they are called cell fate determinants. This mechanism has two requirements: first, the mother cell must be polarized, and second, the mitotic spindle must be aligned with the axis of polarity. The cell biology of these events has been most successfully studied in three animal models: the mouse, the nematode Caenorhabditis elegans, and the fruit fly Drosophila melanogaster.
Most mechanistic insights into asymmetric cell division come from invertebrate experiments. However, discoveries in work on mammalian stem cells have revealed enormous flexibility among the progeny of individual cells. Many different cell fates can be induced by changing growth factors in the culture medium, suggesting that lineage restrictions and intrinsic asymmetries have only minor functions. However, time-lapse video microscopy shows that cortical progenitor cells divide in stereotyped lineages—even in culture, where directional extrinsic signals can be largely excluded. Although there is no clear genetic evidence for intrinsically asymmetric cell divisions in vertebrates, the observation of putative stem cells in intact tissues has revealed several examples for asymmetrically segregating proteins such as Numb and the Notch receptor.
Stem cells constitute a population of cells that continues to divide in organisms and produces cells for tissue generation. Stem cells can self-renew (they produce both differentiating daughters and daughters that maintain stem cell identity) and are pluripotent (they can give rise to all cell types in a given organ). One strategy by which stem cells can accomplish this is asymmetric cell division, whereby each stem cell divides to generate one daughter with a stem cell fate (self-renewal) and one daughter that differentiates. However, asymmetric divisions often give rise to only one novel cell type in addition to a new copy of the mother cell. Self-renewal is a hallmark of stem cells, and there is growing evidence that stem cells self-renew through asymmetric division. In this way, the production of new cell types (differentiation) is precisely balanced by the renewal of the stem cell population. Thus, an asymmetric division is a particularly attractive strategy because it manages both tasks (i.e., self-renewal and differentiation) with a single division. However, a disadvantage of this strategy is that it leaves stem cells unable to expand in number. This lack of flexibility is a problem, given that stem cell numbers can increase markedly, both when stem cell pools are first established during development and when they are regenerated after injury. Therefore, asymmetric cell divisions cannot be the complete story. Stem cells must have additional self-renewal strategies that permit dynamic control of their numbers.
SYMMETRIC
Stem cells can also use symmetric divisions to self-renew and to generate differentiated progeny. Symmetric stem cell divisions have been observed during the development of both invertebrates and vertebrates. Symmetric stem cell divisions are also common during wound healing and regeneration. A hallmark of all three processes is an increase in the number of stem cells. This increase cannot be explained by a strategy restricted to asymmetric cell division, in which only one daughter cell maintains stem cell identity.
Although the idea that stem cells can divide symmetrically may seem counterintuitive, stem cells are defined by their potential to generate more stem cells and differentiated daughters, rather than by their production of a stem cell and a differentiated daughter at each division. When viewed as a population, a pool of stem cells with equivalent developmental potential may produce only stem cell daughters in some divisions and only differentiated daughters in others. The evidence for symmetric stem cell divisions is strong, both in model organisms such as C. elegans and Drosophila and in vertebrates.
SWITCHING
In principle, stem cells can rely either completely on symmetric divisions or on a combination of symmetric and asymmetric divisions. Some mammalian stem cells seem to switch between symmetric and asymmetric cell divisions. For example, neural stem cells change from primarily symmetric divisions that expand stem cell pools during embryonic development to primarily asymmetric divisions that expand differentiated cell numbers in mid- to late gestation. In the developing mammalian cortex, cell divisions are confined to the so-called ventricular zone. Neural precursors divide in the ventricular zone, and daughter cells either stay in this zone and continue to divide or move away from it to differentiate. As layers of differentiated cells arise in the forebrain, neural progenitors increasingly undergo asymmetric division: one cell remains in the ventricular zone (“niche” of stem cells), and the other cell migrates into overlying layers of differentiated neurons. For these cells, divisions are classified as symmetric or asymmetric, depending on whether one or both daughter cells retain the position and morphology associated with stem cells. A caveat, however, is that mammalian stem cells cannot be distinguished from other progenitors on the basis of only morphology and position, so it remains possible that the frequency of asymmetric and symmetric divisions of stem cells differs from that observed in the overall pool of undifferentiated cells.
Switching between symmetric and asymmetric divisions has also been observed in adult mammals. Some adult stem cells seem to divide asymmetrically under steady-state conditions. However, they retain the capacity to divide symmetrically to restore stem cell pools depleted by injury or disease, as has been observed in the nervous and hematopoietic systems. In the subventricular zone of the adult forebrain, for example, asymmetric divisions predominate under steady-state conditions, although some apparently symmetric divisions can be observed. Forebrain loss after stroke increases the rate of division among subventricu-lar zone progenitors, including a rise in symmetric cell divisions that, in turn, leads to increase in neurogenesis. A similar event has been found in the mammalian hematopoietic system. When the hematopoietic system is decimated by chemotherapy, hematopoietic stem cells begin dividing and expand about 10-fold to regenerate pools of both stem cells and differentiated cells. These data suggest that stem cells can facultatively use both symmetric and asymmetric divisions.
The prolonged symmetric divisions of mammalian stem cells during early embryonic development generate large pools of stem cells and tissues. The ability to switch back and forth between symmetric and asymmetric modes of division depends on developmental and environmental cues. A key issue for the future is how stem cells are regulated to switch between asymmetric and symmetric divisions.
