Mitochondria Define Intestinal Stem Cell Differentiation Downstream of a FOXO/Notch Axis

Ludikhuize, Marlies C.; Meerlo, Maaike; Pagès-Gallego, Marc; Xanthakis, Despina; Julià, Mar Burgaya; Nguyen, Nguyen T.B.; Brombacher, Eline C.; Liv, Nalan; Maurice, Madelon M.; Paik, Jihye; Burgering, Boudewijn M.T.; Colman, Maria J. Rodríguez

doi:10.1016/j.cmet.2020.10.005

Cited by 121 publications

(90 citation statements)

References 71 publications

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“…Club cells are known to act as progenitor-type cells, and can differentiate into numerous epithelial subtypes, including goblet cells [ 57 ]. Mitochondrial fission is also known to play a role in regulation of differentiation of various cell types [ 58 , 59 , 60 ]. These data suggest a link between mitochondrial fission and differentiation of club cells into pathological epithelial subtypes.…”

Section: Discussionmentioning

confidence: 99%

DRP1-Mediated Mitochondrial Fission Regulates Lung Epithelial Response to Allergen

Bruno

Kumar

Mark

et al. 2021

IJMS

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Mitochondria regulate a myriad of cellular functions. Dysregulation of mitochondrial control within airway epithelial cells has been implicated in the pro-inflammatory response to allergens in asthma patients. Because of their multifaceted nature, mitochondrial structure must be tightly regulated through fission and fusion. Dynamin Related Protein 1 (DRP1) is a key driver of mitochondrial fission. During allergic asthma, airway epithelial mitochondria appear smaller and structurally altered. The role of DRP1-mediated mitochondrial fission, however, has not been fully elucidated in epithelial response to allergens. We used a Human Bronchial Epithelial Cell line (HBECs), primary Mouse Tracheal Epithelial Cells (MTECs), and conditional DRP1 ablation in lung epithelial cells to investigate the impact of mitochondrial fission on the pro-inflammatory response to house dust mite (HDM) in vitro and in vivo. Our data suggest that, following HDM challenge, mitochondrial fission is rapidly upregulated in airway epithelial cells and precedes production of pro-inflammatory cytokines and chemokines. Further, deletion of Drp1 in lung epithelial cells leads to decreased fission and enhanced pro-inflammatory signaling in response to HDM in vitro, as well as enhanced airway hyper-responsiveness (AHR), inflammation, differential mucin transcription, and epithelial cell death in vivo. Mitochondrial fission, therefore, regulates the lung epithelial pro-inflammatory response to HDM.

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Section: Discussionmentioning

confidence: 99%

DRP1-Mediated Mitochondrial Fission Regulates Lung Epithelial Response to Allergen

Bruno

Kumar

Mark

et al. 2021

IJMS

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“… 6 , 7 , 9 , 36 Very recently differentiation of intestinal stem cells into the secretory lineage has been proposed to depend on mitochondria by a mechanism involving FoxO (Forkhead box O) transcription factors and Notch signaling–regulated mitochondrial fission. 37 Data presented here suggest that loss of p32, which is postulated to be the main driver of OXPHOS, is the underlying cause of metabolic dysfunction and secondarily of defective goblet cell function in UC.…”

Section: Discussionmentioning

confidence: 69%

Loss of Mucosal p32/gC1qR/HABP1 Triggers Energy Deficiency and Impairs Goblet Cell Differentiation in Ulcerative Colitis

Sünderhauf

Hicken

Schlichting

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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Oxidative phosphorylation promoting p32 critically maintains mitochondria function essential for terminal goblet cell differentiation. Reduced colonic p32 expression in ulcerative colitis patients possibly explains a great range of diseasespecific histopathological hallmarks. BACKGROUND & AIMS:Cell differentiation in the colonic crypt is driven by a metabolic switch from glycolysis to mitochondrial oxidation. Mitochondrial and goblet cell dysfunction have been attributed to the pathology of ulcerative colitis (UC). We hypothesized that p32/gC1qR/HABP1, which critically maintains oxidative phosphorylation, is involved in goblet cell differentiation and hence in the pathogenesis of UC.METHODS: Ex vivo, goblet cell differentiation in relation to p32 expression and mitochondrial function was studied in tissue biopsies from UC patients versus controls. Functional studies were performed in goblet cell-like HT29-MTX cells in vitro. Mitochondrial respiratory chain complex V-deficient, ATP8 mutant mice were utilized as a confirmatory model. Nutritional intervention studies were performed in C57BL/6 mice. RESULTS:In UC patients in remission, colonic goblet cell differentiation was significantly decreased compared to controls in a p32-dependent manner. Plasma/serum L-lactate and colonic pAMPK level were increased, pointing at high glycolytic activity and energy deficiency. Consistently, p32 silencing in mucus-secreting HT29-MTX cells abolished butyrate-induced differentiation and induced a shift towards glycolysis. In ATP8 mutant mice, colonic p32 expression correlated with loss of differentiated goblet cells, resulting in a thinner mucus layer. Conversely, feeding mice an isocaloric glucose-free, high-protein diet increased mucosal energy supply that promoted colonic p32 level, goblet cell differentiation and mucus production. CONCLUSION:We here describe a new molecular mechanism linking mucosal energy deficiency in UC to impaired, p32-FLA 5.6.0 DTD JCMGH748 proof 7 May 2021 8:21 am ce OB dependent goblet cell differentiation that may be therapeutically prevented by nutritional intervention.

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“…Our data also suggest that wedelolactone potently increased FOXO1 dependent signaling pathways. FOXO proteins are transcription factors that play important roles in stem cell differentiation [24,25]. The function of FOXO3A in chondrogenic differentiation of MSCs has been well-studied [26,27].…”

Section: Discussionmentioning

confidence: 99%

Wedelolactone promotes the chondrogenic differentiation of mesenchymal stem cells by suppressing EZH2 in both methyltransferase activity-dependent and -independent manner

Qin

Yang

Chen

et al. 2022

Preprint

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Background: Osteoarthritis (OA) is a degenerative disease that leads to the progressive destruction of articular cartilage. Current clinical therapeutic strategies are moderately effective at relieving pain, but often cannot induce chondrocyte differentiation and achieve cartilage regeneration. Wedelolactone, an active chemical ingredient derived from Eclipta alba, has been reported to facilitate osteoblastogenesis but inhibits adipogenesis in MSCs. However, the effects of wedelolactone on chondrogenic differentiation of MSCs remain largely unknown. Methods: Human-induced pluripotent stem cell (iPSC)-derived MSCs and rat bone marrow MSCs were treated with wedelolactone. Then, real-time reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemical staining, and immunofluorescence staining were used to evaluate the effects of wedelolactone on chondrogenic differentiation of MSCs. To explore the potential mechanism of the effects of wedelolactone on chondrogenic differentiation of MSCs, we performed RNA-seq, miRNA-seq, isobaric tags for relative and absolute quantitation (iTRAQ) analysis, and ChIP-qPCR. Results: We demonstrated that wedelolactone had a beneficial effect on the chondrogenic differentiation of human-induced pluripotent stem cell (iPSC)-derived mesenchymal stem cells (MSCs) and rat bone marrow MSCs. Notably, the forkhead box O (FOXO) signaling pathway was upregulated by wedelolactone during chondrogenic differentiation. The FOXO1 inhibitor attenuated the effect of wedelolactone on chondrocyte differentiation. Mechanistically, wedelolactone reduced the enhancer of zeste homolog 2 (EZH2)-mediated histone 3 lysine 27 trimethylation (H3K27me3) on the promoter region of FOXO1 to increase its transcription. Additionally, wedelolactone repressed microRNA (miR)-1271-5p expression in an EZH2-mediated H3K27me3 independent manner. Further, miR-1271-5p post-transcriptionally suppressed FOXO1 expression dependent on the binding of miR-1271-5p to the FOXO1 3′-UTR. Conclusion: These results indicate that wedelolactone suppresses EZH2 to facilitate the chondrogenic differentiation of MSCs by activating the FOXO1 signaling pathway, suggesting that wedelolactone might improve cartilage regeneration in diseases characterized by inflammatory tissue destruction, such as OA.

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Mitochondria Define Intestinal Stem Cell Differentiation Downstream of a FOXO/Notch Axis

Cited by 121 publications

References 71 publications

DRP1-Mediated Mitochondrial Fission Regulates Lung Epithelial Response to Allergen

DRP1-Mediated Mitochondrial Fission Regulates Lung Epithelial Response to Allergen

Loss of Mucosal p32/gC1qR/HABP1 Triggers Energy Deficiency and Impairs Goblet Cell Differentiation in Ulcerative Colitis

Wedelolactone promotes the chondrogenic differentiation of mesenchymal stem cells by suppressing EZH2 in both methyltransferase activity-dependent and -independent manner

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