Signaling Network Centered on mTORC1 Dominates Mammalian Intestinal Stem Cell Ageing
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Signaling Network Centered on mTORC1 Dominates Mammalian Intestinal Stem Cell Ageing Shao-jie Liang 1 & Jia-yi Zhou 1 & Xiu-qi Wang 1 Accepted: 27 October 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract The intestine integrates the function of digestion, absorption, and barrier, which is easily damaged by the external factors upon ageing. The intestinal stem cells (ISCs) exist at the intestinal crypt base and play an indispensable role in intestinal homeostasis and regeneration. The intestine ageing contributes to malabsorption and other associated illnesses, which were considered to be related to ISCs. Here, we summarize the current research progress of mammalian ISCs ageing and pay more attention to the central regulatory role of the mTORC1 signaling pathway in regulating mammalian ISCs ageing, and its related AMPK, FOXO, Wnt signaling pathways. Furthermore, we also discuss the interventions aimed at mTORC1 and its associated signaling pathways, which may provide potential strategies for rejuvenating aged ISCs and the therapy of age-related intestinal diseases. Keywords Ageing . Intestinal stem cells . mTORC1 . AMPK . FOXO . Wnt
Introduction The intestine is the largest immune and endocrine organ as well as the central location for digestion and the absorption of nutrients. The intestinal epithelium renews every 3–5 days. Intestinal stem cells (ISCs) are the driving force of renewal and homeostasis of intestinal epithelial cells, which intercalate with Paneth cells at the base of crypt [1, 2] (Fig. 1). Fastcycling Lgr5+ ISCs and slow-cycling Bmi1+ ISCs are the two primary types of intestinal stem cells [3–5]. Bmi1+ ISCs can be converted into Lgr5+ ISCs to repair tissue damage, they can differentiate into various functional cells (transitamplifying cells, enterocytes, M cells, Paneth cells, goblet cells, Tuft cells, and enteroendocrine cells) to complete the process of epithelial renewal [6, 7] (Fig. 1). Many signaling pathways regulate the self-renewal and differentiation of ISCs, such as the Wnt, Notch, and mTORC1 pathways [8–13]. Wnt and Notch are the two most critical signaling pathways involved in ISC fate decisions. Activation of Wnt signaling is
* Xiu-qi Wang [email protected] 1
College of Animal Science, Guangdong Laboratory for Lingnan Modern Agriculture/Guangdong Provincial Key Laboratory of Animal Nutrition Control/National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, Guangdong, China
considered to be related to the differentiation of secretory cells. While the activation of Notch in combination with Wnt inhibition is supposed to increase the number of intestinal absorbing cells, the mechanism of the fate determination of ISCs needs further study [7, 14] (Fig. 1). Using a threedimensional (3D) cultured model (intestinal organoid) has dramatically improved our understanding of ISCs, and a recently study revealed that there were seven major phenotypes of the intestinal organoid can be used to unrave
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