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Stem cells

To be and not to be

It has long been proposed that stem cells function by dividing to generate an identical daughter cell and a cell that becomes more specialized. New work illustrates such asymmetric division and its molecular basis.

Stem cells have the unique ability to perpetuate themselves while continually replenishing tissues throughout the life of an organism. This ability has long been attributed to a distinctive asymmetry in their division, such that when a stem cell divides, it gives rise to both an exact copy of itself and a new type of cell that will differentiate into mature cells of the tissue. This asymmetry hypothesis — reflecting a 'to be and not to be' fate decision — can be traced back to the embryologist E. B. Wilson and his contemporaries more than a century ago. But direct evidence for asymmetric division has so far been reported in only a few well-defined stem-cell systems. In these cases, the molecular mechanisms that regulate asymmetric division have also been explored. Work by Yamashita and colleagues1, reported in Science, now showcases an elegant example of asymmetric division, and identifies key new molecules involved in the process.

A hefty roadblock to the study of how stem cells divide has been their elusive nature. Stem cells are rare, and physically resemble their differentiating daughter cells, so they are difficult to recognize in a tissue. It is fair to say that even today — and despite rapid progress in stem-cell research — the identity of stem cells in most tissues remains a matter of debate. (Embryonic stem cells, which are well characterized, exist before tissues form.) This 'identity crisis' has been overcome in only a few cases, such as neuroblasts and germline stem cells in the fruitfly Drosophila, and ventricular-zone progenitor cells in the brains of mammalian embryos2,3.

In flies, a neuroblast divides asymmetrically (Fig. 1a) to renew itself and to produce a smaller ganglion mother cell2, which goes on to generate specific nerve cells. In fly ovaries, germline stem cells are always in contact with a subset of signalling cells called cap cells3. These stem cells also divide asymmetrically, producing a stem-cell daughter that retains contact with the cap cells, and a differentiating daughter that is displaced one cell away4 (Fig. 1b). Such oriented asymmetric division has also been demonstrated by electron microscopy for germline stem cells in the fly testis5, where the signalling cells are called hub cells (Fig. 1c). Yamashita et al.1 have used immunofluorescence microscopy to observe a large number of stem-cell divisions (more than 500) in fly testes, nicely confirming the orientation and asymmetry of division.

Figure 1: Stem-cell decisions. a, A dividing fly neuroblast gives rise to a neuroblast and a smaller ganglion mother cell.
figure1

The protein complexes (crescents) at the apical and basal ends of the dividing neuroblast are different, ensuring the asymmetry of division. b, A germline stem cell in the fly ovary, associated with a cap cell, produces a germline stem cell and a cystoblast. The spectrosome (red) anchors one pole of the mitotic spindle to the cap cell to define the orientation of division. c, A germline stem cell in the fly testis, associated with hub cells, produces a daughter germline stem cell and a gonialblast. Yamashita et al.1 have found that the spectrosome is not involved in this division. d, Yamashita et al. propose that the orientation of division in male germline stem cells is determined by the proteins DE-cadherin (Cad), β-catenin, centrosomin (CNN), adenomatous polyposis coli (APC) and an unidentified component, X.

The key question here is: what tells one daughter cell to be a stem cell and the other not to be? For fly neuroblasts, the solution seems to depend solely on the cell itself2. The neuroblasts are derived from embryonic epithelial-type cells, and inherit their polarity, with one end being 'apical' and the other 'basal'. This allows molecules that determine cell fate to be segregated along the apical–basal axis. The mitotic spindle (the structure that separates chromosomes during division) is also oriented along this axis, such that the plane of division is perpendicular to the axis. This means that one daughter cell inherits the apical molecules and remains a neuroblast; the other inherits the basal components and becomes a ganglion mother cell.

But this self-sufficient mechanism does not seem to be enough for most other stem cells. For instance, in fly ovaries, stem cells must remain within the stem-cell 'niche' — in contact with cap cells — to maintain their fate3 (Fig. 1b). Here, the oriented asymmetric division ensures that, following each division, only one daughter cell will have contact with cap cells and so remain a stem cell. A similar situation occurs for male germline stem cells1,5.

So these three types of stem cell share one feature. The orientation of division — in turn determined by the orientation of the spindle — is key to ensuring an asymmetry between the daughter cells, either in their exposure to a niche signal or in their inheritance of fate-regulating molecules. Then what determines spindle orientation? For female germline stem cells, this requires a spherical organelle called the spectrosome4, which at one spindle pole anchors filamentous structures called astral microtubules to the cap cells. But Yamashita et al.1 show that the spectrosome is often not associated with the spindle pole in male germline stem cells, and thus may not orient the asymmetric division. So the function of the spectrosome might depend on the cellular milieu.

What, then, determines spindle orientation in testis stem cells? Previous work on flies had begun to reveal the importance, in other cell divisions, of cell-to-cell junctions called adherens junctions, and of molecules involved in linking the spindle to these junctions. One such molecule in neuroblasts is centrosomin6, a component of the centrosome. (Dividing cells have two centrosomes, one at each pole; they produce the spindle and astral microtubules.) In the ovary, the proteins DE-cadherin and β-catenin are important for anchoring germline stem cells to cap cells7. In embryonic epithelial cells, disrupting adherens junctions causes misorientation of the spindle8, and the adenomatous poliposis coli 2 protein (APC2), a binding partner for β-catenin, binds to adherens junctions8. Finally, APC2 and β-catenin anchor spindles to the periphery in early fruitfly embryos9.

Yamashita et al.1 show that such a linkage may also define the orientation of division of male germline stem cells. They observed that DE-cadherin, β-catenin and APC2 accumulate at the interface between the stem cell and hub cells, where one pole of the stem-cell spindle is pinned (Fig. 1d). In flies with mutations in APC2, spindles become mispositioned, misoriented or detached from the interface. APC1, meanwhile, localizes to centrosomes just before cell division, and in flies with mutations in APC1, spindle orientation and centrosome position are also somewhat perturbed. So the authors suggest that the adherens junctions, via β-catenin and APC2, anchor the astral microtubules of one of the stem cell's centrosomes. This in turn pins the spindle pole in place. Meanwhile, centrosomin and APC1 contribute to the centrosome's function in spindle-pole organization.

Interestingly, in budding yeast, which undergo stem-cell-like divisions, an APC-like protein called Kar9 has a similar role in capturing microtubules. All of these studies suggest that the spindle-anchorage mechanism described above has been conserved for asymmetric stem-cell division during evolution.

Of course, the stereotypical asymmetric division described here is probably not the only way for stem cells to self-renew. For example, certain mammalian stem cells appear to divide symmetrically10. Consequently, both daughter cells may sometimes remain as stem cells, because they are both exposed to the niche signal or receive appropriate fate determinants; sometimes both may differentiate. For these stem cells, self-renewal is based on a probabilistic mechanism. But even though division is oriented at random, the nature of the niche signalling and the localized determinants should be the same as those in the asymmetrically dividing stem cells. So stereotypical stem cells, with their predictable pattern of division, can serve as simplified models of their symmetrically dividing counterparts. The findings of Yamashita et al.1 thus represent exciting progress in understanding both types of stem cell.

References

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