A family business: stem cell progeny join the niche to regulate homeostasis

Abstract

Stem cell niches, the discrete microenvironments in which the stem cells reside, play a dominant part in regulating stem cell activity and behaviours. Recent studies suggest that committed stem cell progeny become indispensable components of the niche in a wide range of stem cell systems. These unexpected niche inhabitants provide versatile feedback signals to their stem cell parents. Together with other heterologous cell types that constitute the niche, they contribute to the dynamics of the microenvironment. As progeny are often located in close proximity to stem cell niches, similar feedback regulations may be the underlying principles shared by different stem cell systems.

Figure 1. Overview of adult stem cells

Adult stem cells are undifferentiated cells found in many organs throughout the human body. They are capable of both long-term self-renewal and generation of the downstream differentiated cells of an organ. They can be categorized into two major groups: those with high turnover and those with low turnover. In tissues with high turnover rates, such as the haematopoietic system, intestine, interfollicular epidermis and hair follicle, stem cells are responsible for maintaining homeostasis and also for repairing damage upon wounding. Stem cells have also been reported in tissues with low or no turnover, such as the brain and the skeletal muscle. In the skeletal muscle, stem cells are mainly reserved for repair after injury. In the brain, stem cells are required for the generation of defined subsets of neurons that migrate to the olfactory bulb (stem cells in the subventricular zone) and for the generation of new neurons upon learning stimulations (stem cells in the subgranular zone). The locations of a number of stem cells and their reported niche components are listed in the table. Niche components derived from stem cells are denoted by asterisks. The question mark denotes a candidate niche component whose precise regulatory role remains to be demonstrated. CAR cells, CXCL12-abundant reticular cells; K6, keratin 6; MSCs, mesenchymal stem cells; T_Reg cells, regulatory T cells.

Figure 2. CySCs contribute to ‘hub’ maintenance

a | Structure of the Drosophila melanogaster testis. The D. melanogaster male germline stem cell niche, located at the apical tip of the testis, hosts two kinds of stem cells: the germline stem cells (GSCs) and the somatic cyst stem cells (CySCs). The ‘hub’ cells at the apical tip are critical niche components. GSCs produce gonialblasts, which undergo synchronous divisions to generate spermatogonia and eventually mature sperm. CySCs generate somatic cyst cells, which surround the gonialblasts and maturing spermatogonia. b | A crucial signalling molecule from the hub is Unpaired (UPD), which activates the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway in adjacent CySCs to promote their self-renewal by activating transcription factors ZFH1 (zinc-finger homeodomain 1) and CHINMO (chronologically inappropriate morphogenesis). In GSCs, the JAK–STAT pathway functions to facilitate their attachment to the hub via adherens junctions. In addition, the Bone morphogenic protein (BMP)–like molecules Decapentaplegic (DPP) and Glass bottom boat (GBB) are secreted from both the hub and the CySCs to activate BMP signalling in GSCs and repress the differentiation factor bag of marbles (bam). Together, this permits GSC self-renewal. c | In some cases, CySCs also generate cells that can contribute to the hub.

Figure 3. The HFSC niche: a dynamic interplay between HFSC progeny and dermal components

a | Hair follicle stem cells (HFSCs) reside in the outer bulge layer. Keratin 6-expressing (K6⁺) inner bulge cells are downstream progeny of HFSCs and express high levels of bone morphogenic protein 6 (BMP6) and fibroblast growth factor 18 (FGF18), which are quiescence-inducing factors for HFSCs. During telogen, subcutaneous adipocytes express BMP2 and dermal fibroblasts express BMP4. Near the end of the resting phase, the dermal papilla produces HFSC-activating factors, including FGF7 and FGF10, BMP inhibitors and transforming growth factor-β2 (TGFβ2) to counteract the inhibitory effects on the niche. TMEFF1 (transmembrane protein with EGF-like and two follistatin-like domains 1) is induced in hair germ cells by TGFβ2 to dampen the suppressive effects of BMPs. In addition, adipocyte precursor cells secrete platelet-derived growth factor-α (PDGFα) to induce the expression of as-yet-unidentified activating factors in the dermal papilla. The macroenviroment of the underlying dermis also participates, progressing to a BMP-low and WNT-high state. b | Once activating signals accumulate over a threshold level, HFSCs at the base of the bulge (the hair germ), begin to proliferate to initiate hair growth (anagen). The dermal papilla is pushed away from the bulge, and HFSCs return to quiescence. Two populations of outer root sheath (ORS) cells are spared at catagen and form a new bulge at telogen: the slow-cycling ORS cells close to the old bulge form the new outer bulge layer, and the faster cycling ORS cells nearer to the matrix differentiate and become the new inner K6⁺ bulge layer.

Figure 4. ISCs generate Paneth cells that promote stem cell proliferation at the base of the intestinal crypt

Lineage-tracing experiments suggest that the Leu-rich repeat-containing G protein-coupled receptor 5-expressing (LGR5⁺) intestinal stem cells (ISCs; shown in green) at the bottom of the crypt generate all of the differentiated lineages of the intestinal epithelium, including their own niche cells — the Paneth cells (shown in yellow). Paneth cells maintain ISCs both in vitro and in vivo. When Paneth cell numbers are reduced owing to mutations or ablations, the numbers of LGR5⁺ ISCs are also reduced accordingly, and the remaining ISCs cluster around the leftover ISCs. WNT3, epidermal growth factor (EGF), transforming growth factor-α (TGFα) and Delta-like ligand 4 (DLL4) are all factors expressed by the Paneth cells and known to influence the maintenance of ISCs either in vivo or in vitro. A slow-cycling population of ISCs, commonly referred to as the ‘+4 ISCs’ owing to their position fourth from the bottom of the crypt (shown in purple), are located at the periphery of the Paneth cell-rich zone and nearest to the bone morphogenic protein (BMP)-expressing mesenchymal cells. Several genes have been identified to be expressed at these cells, including those encoding Polycomb complex subunit BMI1, telomerase reverse transcriptase (TERT) and atypical homeodomain-containing protein HOPX1. Their unique location might also contribute to their slow-cycling status.

Figure 5. The HSC niche: a rich and complex environment

a | Most haematopoietic stem cells (HSCs) reside in the bone marrow, which can be subdivided into endosteal and perivascular niches. HSCs located on the endosteal side tend to be more quiescent, whereas HSCs located at the perivascular side are more active. The most dormant HSCs have been reported to locate near osteoblast progenitors (preosteoblasts). With the exception of osteoclasts, all of the cellular components in the diagram have been reported to modulate HSC behaviour. Two of the downstream HSC progeny, regulatory T cells (T_Reg cells) and macrophages, participate in HSC regulation. T_Reg cells guard HSCs by making the endosteal niche a possible immune-privileged site, thereby protecting HSCs from immune attack. Macrophages are critical for maintaining HSCs in their bone marrow niche. They appear to do so through an indirect mechanism mediated by nestin⁺ mesenchymal stem cells (MSCs) and possibly by osteoblasts. b | Ablation of bone marrow macrophages reduces the levels of several key maintenance factors for HSCs, such as CXC chemokine ligand 12 (CXCL12), angiopoietin 1 (ANGPT1), KIT ligand (KITL) and vascular cell adhesion molecule 1 (VCAM1), that are expressed in paracrine by the nestin⁺ MSCs. Exactly how macrophages signal to the nestin⁺ MSCs to govern this exchange of signals remains to be identified (and thus is represented by a question mark). CAR cell, CXCL12-abundant reticular cell.