Polarity in stem cell division: asymmetric stem cell division in tissue homeostasis

Abstract

Many adult stem cells divide asymmetrically to balance self-renewal and differentiation, thereby maintaining tissue homeostasis. Asymmetric stem cell divisions depend on asymmetric cell architecture (i.e., cell polarity) within the cell and/or the cellular environment. In particular, as residents of the tissues they sustain, stem cells are inevitably placed in the context of the tissue architecture. Indeed, many stem cells are polarized within their microenvironment, or the stem cell niche, and their asymmetric division relies on their relationship with the microenvironment. Here, we review asymmetric stem cell divisions in the context of the stem cell niche with a focus on Drosophila germ line stem cells, where the nature of niche-dependent asymmetric stem cell division is well characterized.

Figure 1.

Mechanisms of asymmetric stem cell division. (A) Asymmetric stem cell division by extrinsic fate determinants (i.e., the stem cell niche). The two daughters of stem cell division will be placed in distinct cellular environments either inside or outside the stem cell niche, leading to asymmetric fate choice. (B) Asymmetric stem cell division by intrinsic fate determinants. Fate determinants are polarized in the dividing stem cells, which are subsequently partitioned into two daughter cells unequally, thus making the division asymmetrical. Self-renewing (red line) and/or differentiation promoting (green line) factors may be involved.

Figure 2.

The anatomy of the Drosophila germ line stem cell (GSC) niche and asymmetric stem cell division. (A) Male GSC niche: GSCs and cyst stem cells (CySCs) are attached to hub cells via adherens junctions (AJs). GSCs divide asymmetrically to self-renew and produce a gonialblast (GB) that initiates the differentiation program. The GB further undergoes four synchronous, transit-amplifying divisions to yield 16 spermatogonia interconnected by the fusome. The spectrosome is a spherical version of the fusome observed in GSCs. A pair of CySCs encapsulates the GSCs and provides signals required for GSC identity. Similar to GSCs, CySCs divide asymmetrically to self-renew and produce cyst cells. Cyst cells exit the cell cycle, a pair of which encapsulates the GB and spermatogonia to promote differentiation. (B) Asymmetric stem cell division of male GSC by centrosome orientation: Upd ligand is secreted from hub cells to activate the JAK-STAT pathway in GSCs and CySCs to specify their stem cell identity. The Zfh-1 transcription factor controls CySC identity. Together with hub cells, CySCs dictate GSC identity. The mitotic spindle is oriented toward the hub cells via positioning of the centrosome. Spectrosomes in male GSCs are not oriented with respect to the hub cells during interphase. EGFR signaling ensures the encapsulation of germ cells by cyst cells. (C) Female GSC niche: GSCs are attached to the cap cells via adherens junctions. GSCs divide asymmetrically to self-renew and produce a cystoblast (CB) that initiates differentiation. The CB divides four times to give rise to 16 germ cells interconnected by the fusome, only one of which becomes an oocyte, whereas the remaining 15 cells become nurse cells. Escort stem cells (ESCs) encapsulate the GSC, while their daughters, escort cells, encapsulate the developing germ cells. Escort cells are later replaced by follicle cells, which are daughters of follicle stem cells (FSCs). (D) Asymmetric stem cell division of female GSC by the spectrosome: BMP signaling and Piwi controls GSC identity via niche-GSC interaction. The mitotic spindle is oriented toward the cap cells via anchoring of one spindle pole to the spectrosome, which localizes consistently to the apical side of GSCs. (Figures are adapted and modified from Fuller and Spradling 2007.)

Figure 3.

Spindle orientation and asymmetric division in Drosophila and mouse neuronal stem cells. (A) In Drosophila neuroblast, spindle is oriented perpendicular to the apical crescent (red line) that contains the Baz (Par3)-Par6-aPKC complex, as well as Pins, Insc, and Gαi, leading to asymmetric stem cell division. The apical crescent is required for spindle orientation, the basal crescent formation and spindle size asymmetry (i.e., the apical half is larger than the basal half). The basal crescent (yellow line) contains fate determinants that promote/allow differentiation such as Numb, Miranda, and Prospero. In the mutants that are defective in spindle orientation, the apical and basal crescents are bisected into two daughters, leading to symmetric stem cell division. Neuroectoderm cells (from which neuroblasts are derived) also have the apical complex, except for Insc. They divide symmetrically by orienting mitotic spindle parallel to the apical crescent. Ectopic expression of Insc in these cells result in the recruitment of Pins to the apical cortex, leading to perpendicular spindle orientataion (Yu et al. 2000). (B) In mammalian (mouse) neuroepithelial cells, the mode of cell division shifts from symmetric to asymmetric during development. The stem cell identity is determined by inheritance of a tiny apical cortex containing cadherin (red line), and thus mitotic spindle does not have to tilt significantly to divide asymmetrically.