Gut stem cell aging is driven by mTORC1 via a p38 MAPK-p53 pathway

He, Dan; Wu, Huijun; Xiang, Jun; Ruan, Xinsen; Peng, Peike; Ruan, Yuanyuan; Chen, Ye Guang; Wang, Yibin; Yu, Qiang; Zhang, Hongbing; Habib, Samy L.; Pinho, Ronald A. De; Liu, Huijuan; Li, Baojie

doi:10.1038/s41467-019-13911-x

Cited by 102 publications

(84 citation statements)

References 56 publications

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“…SHH pathway inhibition significantly reduced mTORC1 activity in parallel with autophagy activation. Among the upstream signals of mTOR (p-AKT, p-AMPK α , p-ERK, and p-p38) 63 – 65 , p-AKT Ser473 likely mediates SHH-autophagy regulation, which was also supported by AM2 mouse data.…”

Section: Discussionmentioning

confidence: 56%

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Overactivated sonic hedgehog signaling aggravates intrauterine adhesion via inhibiting autophagy in endometrial stromal cells

et al. 2020

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Autophagy can be dynamically induced in response to stresses and is an essential, ubiquitous intracellular recycling system that impacts the fate of damaged resident cells, thereby influencing wound healing. Endometrial fibrosis is a form of abnormal wound healing that causes intrauterine adhesion (IUA) and infertility. We previously demonstrated that overactivated sonic hedgehog (SHH) signaling exacerbated endometrial fibrosis, but the role of autophagy in this process is still unknown. Here, we report that impaired autophagy participates in SHH pathway-induced endometrial fibrosis. Endometrial stroma-myofibroblast transition accompanied by autophagy dysfunction was present in both endometrial biopsies of IUA patients and Amhr2cre/+R26-SmoM2+/− (AM2) transgenic mouse. Mechanistically, SHH pathway negatively regulated autophagy through pAKT-mTORC1 in a human endometrial stromal cell line (T-HESCs). Furthermore, SHH pathway-mediated fibrosis was partly counteracted by autophagy modulation in both T-HESCs and the murine IUA model. Specifically, the impact of SHH pathway inhibition (GANT61) was reversed by the pharmacological autophagy inhibitor chloroquine (CQ) or RNA interference of autophagy-related gene ATG5 or ATG7. Similar results were obtained from the murine IUA model treated with GANT61 and CQ. Moreover, promoting autophagy with rapamycin reduced fibrosis in the AM2 IUA model to baseline levels. In summary, defective autophagy is involved in SHH pathway-driven endometrial fibrosis, suggesting a potential novel molecular target for IUA treatment.

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Section: Discussionmentioning

confidence: 56%

“…Experimental control groups included unstained, PE-stained, 7-AAD-stained, and positive dead cells. The cells were detected by a BD LSRFortessa TM flow cytometer and analyzed by FlowJo X software (Becton, Dickinson & Company, San Jose, CA, USA) 65 .…”

Section: Methodsmentioning

confidence: 99%

Overactivated sonic hedgehog signaling aggravates intrauterine adhesion via inhibiting autophagy in endometrial stromal cells

et al. 2020

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“…In the intestinal epithelium, the features of ageing are accompanied by cell cycle changes, oxidative stress and enhanced apoptosis [86]. Ageing of ISCs is driven by mTORC1 [87] as well as decreased activity of the Wnt signalling pathway [88]. In the gut, ageing impairing the balance between stem cell reserve and differentiation [80,89].…”

Section: Paneth Cells Affect Intestinal Stem Cells In Ageingmentioning

confidence: 99%

Plasticity of Paneth cells and their ability to regulate intestinal stem cells

Mei

2020

Stem Cell Res Ther

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Paneth cells (PCs) are located at the bottom of small intestinal crypts and play an important role in maintaining the stability of the intestinal tract. Previous studies reported on how PCs shape the intestinal microbiota or the response to the immune system. Recent studies have determined that PCs play an important role in the regulation of the homeostasis of intestinal epithelial cells. PCs can regulate the function and homeostasis of intestinal stem cells through several mechanisms. On the one hand, under pathological conditions, PCs can be dedifferentiated into stem cells to promote the repair of intestinal tissues. On the other hand, PCs can regulate stem cell proliferation by secreting a variety of hormones (such as wnt3a) or metabolic intermediates. In addition, we summarise key signalling pathways that affect PC differentiation and mutual effect with intestinal stem cells. In this review, we introduce the diverse functions of PCs in the intestine.

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“…Nutrient malabsorption is common among the elderly and often causes illness [ 149 ]. He and coworkers [ 150 ] showed that aging-induced intestinal villus structural and functional decline is regulated by mammalian target of rapamycin complex 1 (mTORC1), which is a sensor of nutrients and growth factors that is highly activated in ISC and progenitor cells in geriatric mice. Their findings revealed that mTORC1 drives aging by augmenting a prominent stress response pathway in ISCs and identified p38 mitogen-activated protein kinase as an anti-aging target downstream of mTORC1 [ 150 ].…”

Section: Future Directionsmentioning

confidence: 99%

Multiple Roles for Cholinergic Signaling from the Perspective of Stem Cell Function

Takahashi

2021

IJMS

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Stem cells have extensive proliferative potential and the ability to differentiate into one or more mature cell types. The mechanisms by which stem cells accomplish self-renewal provide fundamental insight into the origin and design of multicellular organisms. These pathways allow the repair of damage and extend organismal life beyond that of component cells, and they probably preceded the evolution of complex metazoans. Understanding the true nature of stem cells can only come from discovering how they are regulated. The concept that stem cells are controlled by particular microenvironments, also known as niches, has been widely accepted. Technical advances now allow characterization of the zones that maintain and control stem cell activity in several organs, including the brain, skin, and gut. Cholinergic neurons release acetylcholine (ACh) that mediates chemical transmission via ACh receptors such as nicotinic and muscarinic receptors. Although the cholinergic system is composed of organized nerve cells, the system is also involved in mammalian non-neuronal cells, including stem cells, embryonic stem cells, epithelial cells, and endothelial cells. Thus, cholinergic signaling plays a pivotal role in controlling their behaviors. Studies regarding this signal are beginning to unify our understanding of stem cell regulation at the cellular and molecular levels, and they are expected to advance efforts to control stem cells therapeutically. The present article reviews recent findings about cholinergic signaling that is essential to control stem cell function in a cholinergic niche.

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Gut stem cell aging is driven by mTORC1 via a p38 MAPK-p53 pathway

Cited by 102 publications

References 56 publications

Overactivated sonic hedgehog signaling aggravates intrauterine adhesion via inhibiting autophagy in endometrial stromal cells

Overactivated sonic hedgehog signaling aggravates intrauterine adhesion via inhibiting autophagy in endometrial stromal cells

Plasticity of Paneth cells and their ability to regulate intestinal stem cells

Multiple Roles for Cholinergic Signaling from the Perspective of Stem Cell Function

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