MTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Nature (Impact Factor: 41.46). 05/2012; 486(7404):490-5. DOI: 10.1038/nature11163
Source: PubMed


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.

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Available from: Pekka Katajisto, Dec 25, 2013
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    • "However, very little is known about the molecular basis underlying the intestinal cellular responses to nutritional stress. Major signaling pathways such as Wnt/β-catenin [5], PI3K/Akt [6], mTOR/S6K1 [7], and MAPKs [8] govern intestinal cell growth, differentiation, migration and survival in the intestinal mucosa. An intriguing question that has not been fully addressed is whether and how these crucial signaling cascades respond to nutritional deficiency. "
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    ABSTRACT: Nutritional deficiency and stress can severely impair intestinal architecture, integrity and host immune defense, leading to increased susceptibility to infection and cancer. Although the intestine has an inherent capability to adapt to environmental stress, the molecular mechanisms by which the intestine senses and responds to malnutrition are not completely understood. We hereby report that intestinal cell kinase (ICK), a highly conserved serine/threonine protein kinase, is a novel component of the adaptive cell signaling responses to protein malnutrition in murine small intestine. Using an experimental mouse model, we demonstrated that intestinal ICK protein level was markedly and transiently elevated upon protein deprivation, concomitant with activation of prominent pro-proliferation and pro-survival pathways of Wnt/β-catenin, mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK), and protein kinase B (PKB/Akt) as well as increased expression of intestinal stem cell markers. Using the human ileocecal epithelial cell line HCT-8 as an in vitro model, we further demonstrated that serum starvation was able to induce up-regulation of ICK protein in intestinal epithelial cells in a reversible manner, and that serum albumin partially contributed to this effect. Knockdown of ICK expression in HCT-8 cells significantly impaired cell proliferation and down-regulated active β-catenin signal. Furthermore, reduced ICK expression in HCT-8 cells induced apoptosis through a caspase-dependent mechanism. Taken together, our findings suggest that increased ICK expression/activity in response to protein deprivation likely provides a novel protective mechanism to limit apoptosis and support compensatory mucosal growth under nutritional stress.
    Full-text · Article · Sep 2014 · PLoS ONE
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    • "In mice, chronic calorie restriction (CR) promotes the self-renewal of intestinal stem cells, muscle stem cell engraftment and neural regeneration, preserves the long-term regenerative capacity of HSCs, and prevents the decline of HSC number during aging in certain mouse strains (Lee et al., 2002; Bondolfi et al., 2004; Cerletti et al., 2012; Chen et al., 2003; Ertl et al., 2008; Rafalski and Brunet, 2011; Yilmaz et al., 2012). Reduction of mTOR signaling has been implicated as one of the major molecular mechanisms responsible for the effects of CR on enhanced stem cell function (Huang et al., 2012; Rafalski and Brunet, 2011; Yilmaz et al., 2012). However, neither CR nor other dietary intervention had previously been shown to promote a coordinated effect leading to the regeneration and/or rejuvenation of a major portion of a system or organ. "
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    ABSTRACT: Immune system defects are at the center of aging and a range of diseases. Here, we show that prolonged fasting reduces circulating IGF-1 levels and PKA activity in various cell populations, leading to signal transduction changes in long-term hematopoietic stem cells (LT-HSCs) and niche cells that promote stress resistance, self-renewal, and lineage-balanced regeneration. Multiple cycles of fasting abated the immunosuppression and mortality caused by chemotherapy and reversed age-dependent myeloid-bias in mice, in agreement with preliminary data on the protection of lymphocytes from chemotoxicity in fasting patients. The proregenerative effects of fasting on stem cells were recapitulated by deficiencies in either IGF-1 or PKA and blunted by exogenous IGF-1. These findings link the reduced levels of IGF-1 caused by fasting to PKA signaling and establish their crucial role in regulating hematopoietic stem cell protection, self-renewal, and regeneration.
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    • "CD157 is also involved in the pathophysiology of various diseases, such as the survival of B cells in rheumatoid arthritis, the progression of leukaemia and metastasis of human ovarian carcinoma cells (Kaisho et al., 1994; Shimaoka et al., 1998; Ishihara and Hirano, 2000; Ortolan et al., 2010; Quarona et al., 2013; Lo Buono et al., 2014). In addition, a new role for CD157 has been reported in stem cells: CD157 induces the catalysis of cyclic ADP-ribose in paneth cells, which promotes intestinal stem cell self-renewal in mice on a calorie-restricted diet (Yilmaz et al., 2012); or lung stem/progenitor cells express CD157 (Wu et al., 2013). However, these reports revealed little or no information concerning the relationship with brain function or brain deficits in PD. "
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    ABSTRACT: CD157, known as bone marrow stromal cell antigen-1, is a glycosylphosphatidylinositol-anchored ADP-ribosyl cyclase that supports the survival and function of B-lymphocytes and hematopoietic or intestinal stem cells. Although CD157/Bst1 is a risk locus in Parkinson's disease (PD), little is known about the function of CD157 in the nervous system and contribution to PD progression. Here, we show that no apparent motor dysfunction was observed in young knockout (CD157 (-/-)) male mice under less aging-related effects on behaviors. CD157 (-/-) mice exhibited anxiety-related and depression-like behaviors compared with wild-type mice. These behaviors were rescued through treatment with anti-psychiatric drugs and oxytocin. CD157 was weakly expressed in the amygdala and c-Fos immunoreactivity in the amygdala was less evident in CD157 (-/-) mice than in wild-type mice. These results demonstrate for the first time that CD157 plays a role as a neuro-regulator and suggest a potential role in pre-motor symptoms in PD.
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