Adhesion in the stem cell niche: biological roles and regulation

Shuyi Chen Michelle Lewallen Ting Xie T N E M P O L E V E D - Summary Stem cell self-renewal is tightly controlled by the concerted action of stem cell-intrinsic factors and signals within the niche. Niche signals often function within a short range, allowing cells in the niche to self-renew while their daughters outside the niche differentiate. Thus, in order for stem cells to continuously self-renew, they are often anchored in the niche via adhesion molecules. In addition to niche anchoring, however, recent studies have revealed other important roles for adhesion molecules in the regulation of stem cell function, and it is clear that stem cell-niche adhesion is crucial for stem cell self-renewal and is dynamically regulated. Here, we highlight recent progress in understanding adhesion between stem cells and their niche and how this adhesion is regulated. Introduction Various populations of adult stem cells reside in the body and undergo continuous self-renewal throughout an organisms lifespan. The complex milieu composed of cells and extracellular matrix (ECM), as well as the signaling molecules associated with each population of stem cells, is collectively referred to as the stem cell niche (Spradling et al., 2001). The physical structure of the niche varies between organisms and between stem cell types, its composition ranging from a single cell or cell type to many cells of varying cell types. In the C. elegans hermaphrodite gonad, for example (Fig. 1A), a single cell, known as the distal tip cell, functions as the niche for germline stem cells (GSCs) (Byrd and Kimble, 2009; Kimble and Crittenden, 2007). By contrast, in the Drosophila ovary (Fig. 1B) and testis (Fig. 1C), two or three somatic cell types form the niche for GSCs: the female GSC niche is composed of terminal filament cells, cap cells and GSCcontacting escort cells, whereas the male niche consists of hub cells and cyst stem cells (CySCs) (de Cuevas and Matunis, 2011; Xie, 2012). Sometimes, two different stem cell types in the same tissue share a common niche cell component. For example, cap cells in the Drosophila ovary serve as a component of both the GSC and follicular stem cell (FSC) niches, whereas hub cells of the testis function as the common niche component that regulates GSCs and CySCs (de Cuevas and Matunis, 2011; Xie, 2012). Mammalian stem cell niches are generally more complex. The hematopoietic stem cell (HSC) niche contains at least four different cell types (Fig. 1D), including osteoblasts, vascular cells, mesenchymal stem cells and neuron-Schwann cells (Wang and Wagers, 2011). In addition to specialized cell types, the ECM is a crucial component of the stem cell niche; many stem cell types, such as mammalian spermatogonial stem cells (SSCs), epidermal stem cells and neural stem cells (NSCs) (Fig. 1E), express high levels of integrins and directly contact the ECM, highlighting the role of ECM as an integral part of the stem cell niche (Kanatsu-Shinohara et al., 2008; Kazanis et al., 2010; Shen et al., 2008; Watt, 2002). This complex nature of the stem cell niche allows the formation of distinct and specialized niche structures for different stem cell types in the same organism or for the same stem cell type in different organisms. Individual stem cell niches also use distinct combinations of signaling molecules to control stem cell self-renewal and proliferation. For some stem cell types, the activation of a single signaling pathway by the niche is sufficient for promoting stem cell self-renewal. For example, bone morphogenetic protein (BMP) in the Drosophila female GSC niche is necessary and sufficient for GSC self-renewal (Xie, 2012). This is also true for Notch in the C. elegans GSC niche (Byrd and Kimble, 2009; Kimble and Crittenden, 2007). However, for most stem cell types, the simultaneous activation of several pathways is needed for continuous stem cell self-renewal. For example, the fibroblast growth factor (FGF), brain-derived neurotrophic factor (BDNF) and sonic hedgehog (Shh) signaling pathways are needed for longterm mammalian NSC self-renewal in vivo (Zhao et al., 2008). Although specific signals or combinations of signals are needed by different niches to control stem cell self-renewal, many of them appear to function as short-range signals. Thus, stem cells must stay inside the niche in order to maintain long-term self-renewal. One of the most convenient, and arguably the most reliable, methods is to anchor stem cells in their niche using adhesion molecules. In this Review, we summarize recent progress in understanding how stem cells are maintained in their niche, and we highlight how adhesion molecules contribute to cell-cell adhesion and cell-niche anchorage as well as to other aspects of stem cell regulation. Classes of adhesion molecules that mediate stem cell-niche interactions The cadherin family of adhesion proteins Classical cadherin molecules mediate cell-cell adhesion via homophilic interactions between the extracellular domains of cadherins on adjacent cells and via interactions of cadherin intracellular domains with cytoskeleton-associated proteins. The intracellular domains of cadherins can interact with -catenin and -catenin, which are scaffold proteins that connect cadherins to the cytoskeletal network in order to cluster cadherin molecules and form stable adherens junctions (AJs) (Gates and Peifer, 2005; Leckband and Sivasankar, 2012; Meng and Takeichi, 2009). The best-studied molecule involved in stem cell-niche adhesion is Ecadherin. In the Drosophila ovary, E-cadherin was first shown to accumulate at the junction between GSCs and their niche cells (the A C. elegans gonad B Drosophila ovary C Drosophila testis D Mammalian HSC niche E Mammalian NSC niche Fig. 1. Stem cell niches. Niche cells and stem cells are depicted in green and red, respectively. Differentiated stem cell progeny and their surrounding somatic cells are shown in yellow and gray, respectively. (A)The GSC niche in the C. elegans hermaphrodite gonad. (B)The GSC niche in the Drosophila ovary. (C)The GSC niche in the Drosophila testis. (D)The mammalian HSC niche. (E)The NSC niche in the mammalian subventricular zone. ASC, astrocyte; CAR, CXCL12-abundant reticular cell; CPC, cap cell; CySC, cyst stem cell; DGCs, differentiated germ cells; DTC, distal tip cell; EPC, ependymal cell; GEC, GSC-contacting escort cell; GSC, germline stem cell; HSC, hematopoietic stem cell; LSC, leptin receptor+ perivascular stromal cell; MSC, mesenchymal stem cell; NBs, neuroblasts; NSC, neural stem cell; PEC, posterior escort cell; SNC-SC, sympathetic neuronal cell-Schwann cell; SNO, spindle-shaped N-cadherin+ osteoblast; TF, terminal filament. cap cells) and form AJs (Song et al., 2002). In addition, E-cadherin also accumulates between FSCs and their niche cells (Song and Xie, 2002). The removal of E-cadherin from GSCs or FSCs leads to rapid GSC or FSC departure from the niche, indicating that Ecadher (...truncated)