SIRT2 Contributes to the Regulation of Intestinal Cell Proliferation and Differentiation

Abstract

Using complementary approaches (intestinal epithelial cell lines, intestinal organoids and SIRT2 knockout mice), we demonstrated that SIRT2, decreased in intestinal tissues from patients with inflammatory bowel diseases, contributes to the maintenance of intestinal epithelium homeostasis through regulation of Wnt-b-catenin signaling. BACKGROUND AND AIMS: Intestinal mucosa undergoes a continual process of proliferation, differentiation, and apoptosis. Disruption of this homeostasis is associated with disorders such as inflammatory bowel disease (IBD). We investigated the role of Sirtuin 2 (SIRT2), a NAD-dependent protein deacetylase, in intestinal epithelial cell (IEC) proliferation and differentiation and the mechanism by which SIRT2 contributes to maintenance of intestinal cell homeostasis. METHODS: IECs were collected from SIRT2-deficient mice and patients with IBD. Expression of SIRT2, differentiation markers (mucin2, intestinal alkaline phosphatase, villin, Na,K-ATPase, and lysozyme) and Wnt target genes (EPHB2, AXIN2, and cyclin D1) was determined by western blot, real-time RT-PCR, or immunohistochemical (IHC) staining. IECs were treated with TNF or transfected with siRNA targeting SIRT2. Proliferation was determined by villus height and crypt depth, and Ki67 and cyclin D1 IHC staining. For studies using organoids, intestinal crypts were isolated. RESULTS: Increased SIRT2 expression was localized to the more differentiated region of the intestine. In contrast, SIRT2 deficiency impaired proliferation and differentiation and altered stemness in the small intestinal epithelium ex vivo and in vivo. SIRT2-deficient mice showed decreased intestinal enterocyte and goblet cell differentiation but increased the Paneth cell lineage and increased proliferation of IECs. Moreover, we found that SIRT2 inhibits Wnt/b-catenin signaling, which critically regulates IEC proliferation and differentiation. Consistent with a distinct role for SIRT2 in maintenance of gut homeostasis, intestinal mucosa from IBD patients exhibited decreased SIRT2 expression. CONCLUSION: We demonstrate that SIRT2, which is decreased in intestinal tissues from IBD patients, regulates Wnt-b-catenin signaling and is important for maintenance of IEC proliferation and differentiation.

Neurotensin Regulates Proliferation and Stem Cell Function in the Small Intestine in a Nutrient-Dependent Manner

“… 75 Cyclin–cyclin-dependent kinase complexes regulate the switch from active cell proliferation to terminal differentiation, and cyclin D1 expression is correlated inversely with goblet cell differentiation in multiple mouse models. 76 , 77 , 78 Thus, attenuation of cyclin D1 expression associated with the absence of NT may shift the balance from progenitor cell proliferation to terminal differentiation. Together, these data suggest that the trophic effects of NT in the small intestine are mediated, in part, by positive regulation of ERK1/2 signaling and cell-cycle progression.…”

Analysis of Sirtuin 1 and Sirtuin 3 at Enzyme and Protein Levels in Human Breast Milk during the Neonatal Period

“…Mechanistically, sirtuin in breast milk may have a local effect on the gut, regulating for example, metabolic processes and the metabolome, cell signaling, and transport across intestinal membranes. Sirtuins were shown to have an effect on the regulation of proliferation and differentiation of intestinal cells [29], the intestinal microbiota [26,28], and intestinal inflammation [28]. Modulation of the enteric nervous system by sirtuins has been suggested to impact the brain via the microbiota-gut-brain axis [26].…”

“…Additionally, sirtuins 1, 2, and 3 have been shown to modulate neurodegeneration in the enteric nervous system [26] and may impact the brain by the microbiota-gut-brain axis, which has been suggested to be involved in priming important organ systems via early-life nutrition [27]. Sirtuin 1 was reported to regulate the gut microbiota [28], sirtuin 2 was found to maintain gut homeostasis [29], while sirtuin 1 is supposed to be involved in the pathophysiology of necrotizing enterocolitis [30].…”

Sirt1 Is a Regulator of Autophagy in Intestinal Cells

“…Крім того, SIRT2 інгібує Wnt/β-катенін -сигнальний шлях, що регулює проліферацію та диференціювання стовбурових епітеліальних клітин. Отже, SIRT2 підтримує гомеостаз клітин кишечника [28]. SIRT3, SIRT4 і SIRT5 називають мітохондріальними сиртуїнами [25].…”