mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake

Abstract

SUMMARY How adult tissue stem and niche cells respond to the nutritional state of an organism is not well understood. Here, we find that Paneth cells, a key constituent of the mammalian intestinal stem cell (ISC) niche, augment stem cell function in response to calorie restriction (CR). CR acts by reducing mTOR complex 1 (mTORC1) signaling in Paneth cells, and the ISC-enhancing effects of CR can be mimicked by rapamycin. Calorie intake regulates mTORC1 in Paneth cells, but not ISCs, and forced mTORC1 activation in Paneth cells during CR abolishes their effects on ISCs. Finally, increased expression in Paneth cells of bone stromal antigen 1 (Bst-1), an ectoenzyme that produces the paracrine factor cyclic ADP ribose (cADPR), mediates the effects of CR and rapamycin on ISC function. Our findings establish that mTORC1 non-cell autonomously regulates stem cell self-renewal, and highlight a significant role of the mammalian intestinal niche in coupling stem cell function to organismal physiology.

Beyond growth signaling: Paneth cells metabolically support ISCs

“…This kind of metabolic interdependence is consistent with the previously elucidated response of Paneth cells and CBCs to caloric restriction [10]. Under conditions of caloric restriction in mice, the intestinal villi shorten and contain fewer differentiated absorptive cells, enterocytes.…”

YY1 is indispensable for Lgr5 + intestinal stem cell renewal

“…Indeed, recent work has implicated the mTOR pathway in homoestatic control of Lgr5 + stem cell numbers based on nutrient availability (16). PGC-1α is also necessary for intestinal stem cell (ISC) renewal in Drosophila (19), suggesting that the process is conserved across species.…”

“…There is a clear imperative to understand the regulatory mechanisms governing intestinal stem cell function. Recent work has shown that intestinal stem cells from both flies and humans are sensitive to the metabolic state of the organism and has implicated cellular metabolism as a critical regulatory input of stem cell homeostasis (13)(14)(15)(16). Intestinal stem cells were observed to exhibit higher levels of glycolysis than oxidative phosphorylation compared with their differentiated progeny (17), and the oxidative state of intestinal stem cells impacts the ability of the cells to undergo transformation (18).…”

“…Intestinal stem cells were observed to exhibit higher levels of glycolysis than oxidative phosphorylation compared with their differentiated progeny (17), and the oxidative state of intestinal stem cells impacts the ability of the cells to undergo transformation (18). Caloric restriction was recently shown to increase intestinal stem cell numbers (16). In Drosophila, intestinal stem cell expression of the fly homolog to PGC-1α, a metabolic coregulator, is even coupled to the organism's lifespan (19).…”

mTOR Signaling in Growth, Metabolism, and Disease

“…A related possibility is that inhibition of mTORC1 slows aging by increasing autophagy, which helps clear damaged proteins and organelles such as mitochondria, the accumulation of which are also associated with aging and aging-related diseases. Finally, another model suggests that the attenuation of adult stem cells in various tissues plays a central role in organismal aging, and mTOR inhibition boosts the self-renewal capacity of both hematopoietic and intestinal stem cells in mice (Chen et al, 2009;Yilmaz et al, 2012). Ultimately, the importance of mTORC1 signaling in aging likely reflects its unique capacity to regulate such a wide variety of key cellular functions (Fig 5C).…”