Control of adult stem cells in vivo by a dynamic physiological environment: diet-dependent systemic factors in Drosophila and beyond

Abstract

Adult stem cells are inextricably linked to whole-body physiology and nutrient availability through complex systemic signaling networks. A full understanding of how stem cells sense and respond to dietary fluctuations will require identifying key systemic mediators, as well as elucidating how they are regulated and integrated with local and intrinsic factors across multiple tissues. Studies focused on the Drosophila germline have generated valuable insights into how stem cells are controlled by diet-dependent pathways, and increasing evidence suggests that diverse adult stem cell populations respond to nutrients through similar mechanisms. Systemic signals, including nutrients themselves and diet-regulated hormones such as Insulin/Insulin-like growth factor or steroid hormones, can directly or indirectly affect stem cell behavior by modifying local cell-cell communication or intrinsic factors. The physiological regulation of stem cells in response to nutritional status not only is a fascinating biological problem, but also has clinical implications, as research in this field holds the key to noninvasive approaches for manipulating stem cells in vivo. In addition, given the known associations between diet, stem cells, and cancer risk, this research may inspire novel anticancer therapies.

FIGURE 1

Examples of adult stem cells influenced by whole-body physiology. (a) Drosophila female GSCs reside in a specialized niche (yellow), and their differentiating progeny (blue) are intimately associated with somatic escort cells (purple). FSCs give rise to follicle cells (green) that surround germ cells to form follicles. (b) GSCs (enveloped by cyst progenitor cells) in the Drosophila testis reside in the hub niche; the differentiating GSC progeny (blue) are enveloped by cyst cells. (c) Mammalian ISCs in the intestinal crypts generate transit amplifying cells (blue) that give rise to differentiated cells including Paneth cells, thought to serve as the ISC niche. Crypts are in close proximity to blood vessels (red) and other differentiated cells. (d) Mammalian HSCs reside in a niche composed of MSCs, vasculature (red), and other differentiated cells in the bone marrow, and HSCs can also be mobilized into the bloodstream. See references for detailed descriptions.

FIGURE 2

Possible mechanisms for dietary regulation of adult stem cells. (a) Nutrients may directly stimulate stem cells. (b-d) Alternatively, nutrients may affect stem cells through the direct action of systemic hormones (b), or through indirect effects of nutrients and/or systemic hormones acting on adjacent cells to modulate local signaling (c). Most likely, stem cell activity is regulated by a complex web of signaling (d), including all of the above mechanisms and additional hormonal crosstalk and signaling relays. The stem cell itself may also signal back to the niche or influence hormonal production indirectly (hatched lines) as a result of the function of its differentiated progeny.

FIGURE 3

Integration of conserved nutrient-sensing pathways. Cells respond to Insulin/IGF and amino acids via the Insulin receptor (InR) and TOR pathways, which share common downstream effectors to control cell growth, proliferation, and survival. Insulin receptor substrate (IRS) is a major direct target of InR. AMPK, which is activated by LKB1 under low intracellular ATP levels, and SIRTs, which require NAD⁺, also interact with the InR and TOR pathways. See references^{, ,} for in-depth description of pathways.

FIGURE 4

Working model for Drosophila female GSC regulation by diet-dependent signaling. Insulin-like peptides (ILPs) act directly on GSCs to control their proliferation, but indirectly promote GSC maintenance through the niche. TOR signaling controls GSC proliferation, and optimal TOR activity is also required for GSC maintenance by modulating BMP signaling. Ecdysone directly stimulates GSC division and maintenance; ecdysone signaling functions with the NURF chromatin remodeler to stimulate the GSC response to niche BMP signals. In addition, ecdysone also acts on escort cells to promote differentiation of GSC daughters; this function is similar to that described for LSD1. For details, see text and references^{, , , , , , , , ,} .

FIGURE 5

Model for interaction between NHRs and the epigenetic machinery. (a) In the absence of ligand, heterodimeric NHRs are bound by co-repressors, inhibiting transcription at target promoters (pink line). (b) Upon ligand-induced activation, chromatin remodelers replace co-repressors, promoting relaxation of the histone (light green)-DNA (blue) interaction or an open chromatin configuration via nucleosome sliding. (c,d) Transcription is facilitated by (c) open DNA at target promoters to allow the binding of additional target-specific transcription factors (e.g., FOXO, MAD, STAT, or Notch), thus promoting indirect transactivation of target genes, or by (d) direct transactivation of target genes by the NHR complex. Chromatin remodelers could also be exchanged for other NHR co-activators (c) that potentiate the transcriptional response.