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

By Ömer H. Yilmaz, P. Katajisto, Dudley Lamming, Yetiş Gültekin, K. Bauer-Rowe, Shomit Sengupta, Kıvanç Birsoy, Abdulmetin Dursun, V. O. Yilmaz, M. Selig and 6 more. Nature, 2012

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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. Calorie restriction acts by reducing mechanistic target of rapamycin complex 1 (mTORC1) signalling in Paneth cells, and the ISC-enhancing effects of calorie restriction can be mimicked by rapamycin. Calorie intake regulates mTORC1 in Paneth cells, but not ISCs, and forced activation of mTORC1 in Paneth cells during calorie restriction abolishes the ISC-augmenting effects of the niche. Finally, increased expression of bone stromal antigen 1 (Bst1) in Paneth cells—an ectoenzyme that produces the paracrine factor cyclic ADP ribose—mediates the effects of calorie restriction 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.

Subfields: Genetics, Oncology, Physiology

View Paper: https://www.semanticscholar.org/paper/884ee5a217287af564714b898f0d1ba81d3896db

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Citations in the corpus

Metabolic Control of Longevity. (2016, background): “This has been demonstrated in intestinal stem cells, whose function is improved by MTORC1 inhibition in Paneth cells (Yilmaz et al., 2012).”
The intestinal crypt, a prototype stem cell compartment. (2013, background): “This ‘‘doublet assay’’ has meanwhile been exploited to demonstrate that Paneth cells monitor the metabolic state to fine-tune stem cell activity (Yilmaz et al., 2012).”
The hallmarks of aging. (2013, background): “In particular, mTORC1 inhibition with rapamycin, which can postpone aging by improving proteostasis (see ‘‘Loss of Proteostasis’’) and by affecting energy sensing (see ‘‘Deregulated Nutrient Sensing’’), may also improve stem cell function in the epidermis, in the hematopoietic system, and in the int”
Metabolic Plasticity in Stem Cell Homeostasis and Differentiation (2012, neutral): “, 2010), by hypoxia (Yoshida et al., 2009), through inhibition of the p53 pathway (Bensaad et al.”
Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease (2023, background): “180,181 The depletion of foxo was found to restore stem cell aging in germline stem cells of drosophila.”
mTOR Signaling in Growth, Metabolism, and Disease (2017, background): “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).”
mTOR Signaling in Growth, Metabolism, and Disease. (2017, background): “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).”