Intestinal stem cell dynamics in homeostasis and cancer

Ramadan, Rana; Driel, Milou S. van; Vermeulen, Louis; Neerven, Sanne M. van

doi:10.1016/j.trecan.2022.01.011

Cited by 20 publications

(10 citation statements)

References 90 publications

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“…Furthermore, our previously study found that Fut2 deficiency in IECs promote colorectal cancer (CRC) progression in a dextran sulfate sodium/azoxymethane (DSS/AOM) mouse model [ 44 ]. Given the strong connection between dysfunctional ISCs and cancer development [ 45 ], whether Fut2 deficiency in ISCs contributes to the pathogenesis of CRC during aging may be a meaningful question in future studies.…”

Section: Discussionmentioning

confidence: 99%

Fut2 Deficiency Promotes Intestinal Stem Cell Aging by Damaging Mitochondrial Functions via Down-Regulating α1,2-Fucosylation of Asah2 and Npc1

Duan,

Wang,

et al. 2024

Research

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Fut2-mediated α1,2-fucosylation is important for gut homeostasis, including the intestinal stem cell (ISC). The stemness of ISC declines with age, and aging-associated ISC dysfunction is closely related to many age-related intestinal diseases. We previously found intestinal epithelial dysfunction in some aged Fut2 knockout mice. However, how Fut2-mediated α1,2-fucosylation affects ISC aging is still unknown. On this basis, the herein study aims to investigate the role of Fut2-mediated α1,2-fucosylation in ISC aging. Aging models in ISC-specific Fut2 knockout mice were established. ISCs were isolated for proteomics and N-glycoproteomics analysis. ISC functions and mitochondrial functions were examined in mice and organoids. Ulex europaeus agglutinin I chromatography and site-directed mutagenesis were used to validate the key target fucosylated proteins of Fut2. As a result, Fut2 knockout impaired ISC stemness and promoted aging marker expression in aged mice. Proteomics analysis indicated mitochondrial dysfunction in Fut2 knockout ISC. More injured mitochondria, elevated levels of reactive oxygen species, and decreased levels of adenosine 5′-triphosphate (ATP) in Fut2 knockout ISC were found. Moreover, respiratory chain complex impairment and mitophagy dysfunction in Fut2 knockout ISC were further noted. Finally, Fut2 was demonstrated to regulate mitochondrial functions mainly by regulating the α1,2-fucosylation of N -acyl sphingosine amidohydrolase 2 (Asah2) and Niemann–Pick type C intracellular cholesterol transporter 1 (Npc1). In conclusion, this study demonstrated the substantial role of Fut2 in regulating ISC functions during aging by affecting mitochondrial function. These findings provide novel insights into the molecular mechanisms of ISC aging and therapeutic strategies for age-related intestinal diseases.

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Section: Discussionmentioning

confidence: 99%

Fut2 Deficiency Promotes Intestinal Stem Cell Aging by Damaging Mitochondrial Functions via Down-Regulating α1,2-Fucosylation of Asah2 and Npc1

Duan,

Wang,

et al. 2024

Research

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“…This was particularly evident at the tumor edge, alluding to the supply of factors at the stroma tumor interface. This shows that micro-environmental components contribute essential signals to support clonal expansion [ 63 ]. Our results are in line with this observation when it comes to the micro-environmental impact on clonal selection.…”

Section: Discussionmentioning

confidence: 99%

Modeling Colorectal Cancer Progression Reveals Niche-Dependent Clonal Selection

Vaquero-Siguero

Schleußner

Volk

et al. 2022

Cancers

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Colorectal cancer (CRC) is among the deadliest cancers worldwide, with metastasis being the main cause of patient mortality. During CRC progression the complex tumor ecosystem changes in its composition at virtually every stage. However, clonal dynamics and associated niche-dependencies at these stages are unknown. Hence, it is of importance to utilize models that faithfully recapitulate human CRC to define its clonal dynamics. We used an optical barcoding approach in mouse-derived organoids (MDOs) that revealed niche-dependent clonal selection. Our findings highlight that clonal selection is controlled by a site-specific niche, which critically contributes to cancer heterogeneity and has implications for therapeutic intervention.

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“…Under normal circumstances, intestinal mucosal cells can rapidly self-renewed within 5 days in human body. Intestinal mucosal cells can present proliferation, differentiation, damage repair and apoptosis simultaneously (Ramadan et al, 2022). The homeostasis of normal intestine has been explained to be dependent on mitochondrial function: Undifferentiated stem cells use glycolysis to generate ATP, whereas along crypt-villus axis, ATP production shifts from glycolysis to mitochondrial oxidative phosphorylation.…”

Section: Figurementioning

confidence: 99%

Pathogenesis and therapy of radiation enteritis with gut microbiota

et al. 2023

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Radiotherapy is widely used in clinic due to its good effect for cancer treatment. But radiotherapy of malignant tumors in the abdomen and pelvis is easy to cause radiation enteritis complications. Gastrointestinal tract contains numerous microbes, most of which are mutualistic relationship with the host. Abdominal radiation results in gut microbiota dysbiosis. Microbial therapy can directly target gut microbiota to reverse microbiota dysbiosis, hence relieving intestinal inflammation. In this review, we mainly summarized pathogenesis and novel therapy of the radiation-induced intestinal injury with gut microbiota dysbiosis and envision the opportunities and challenges of radiation enteritis therapy.

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Intestinal stem cell dynamics in homeostasis and cancer

Cited by 20 publications

References 90 publications

Fut2 Deficiency Promotes Intestinal Stem Cell Aging by Damaging Mitochondrial Functions via Down-Regulating α1,2-Fucosylation of Asah2 and Npc1

Fut2 Deficiency Promotes Intestinal Stem Cell Aging by Damaging Mitochondrial Functions via Down-Regulating α1,2-Fucosylation of Asah2 and Npc1

Modeling Colorectal Cancer Progression Reveals Niche-Dependent Clonal Selection

Pathogenesis and therapy of radiation enteritis with gut microbiota

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