The Role of pHi in Intestinal Epithelial Proliferation–Transport Mechanisms, Regulatory Pathways, and Consequences

Amiri, Mahdi; Seidler, Ursula; Nikolovska, Katerina

doi:10.3389/fcell.2021.618135

Cited by 5 publications

(3 citation statements)

References 86 publications

(89 reference statements)

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“…Additionally, in vivo studies confirm that increased pHi is necessary for the differentiation of Drosophila follicle stem cells 6 , 8 , melanocytes during zebrafish neural crest development 2 , and mesoderm progenitors in the chicken embryo 7 . Similar to our findings, an increasing pHi gradient is seen in murine colonic crypts 27 , 62 . However, reducing pHi in colonic crypts is associated with decreased expression of absorptive fate genes and increased Goblet cell and Paneth cell markers 27 , which is in contrast to our findings in the small intestine.…”

Section: Discussionsupporting

confidence: 92%

Intracellular pH dynamics regulates intestinal stem cell lineage specification

et al. 2023

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Intracellular pH dynamics is increasingly recognized to regulate myriad cell behaviors. We report a finding that intracellular pH dynamics also regulates adult stem cell lineage specification. We identify an intracellular pH gradient in mouse small intestinal crypts, lowest in crypt stem cells and increasing along the crypt column. Disrupting this gradient by inhibiting H+ efflux by Na+/H+ exchanger 1 abolishes crypt budding and blocks differentiation of Paneth cells, which are rescued with exogenous WNT. Using single-cell RNA sequencing and lineage tracing we demonstrate that intracellular pH dynamics acts downstream of ATOH1, with increased pH promoting differentiation toward the secretory lineage. Our findings indicate that an increase in pH is required for the lineage specification that contributes to crypt maintenance, establishing a role for intracellular pH dynamics in cell fate decisions within an adult stem cell lineage.

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Section: Discussionsupporting

confidence: 92%

Intracellular pH dynamics regulates intestinal stem cell lineage specification

et al. 2023

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“…Additionally, in vivo studies confirm that increased pHi is necessary for differentiation of Drosophila follicle stem cells (Benitez et al, 2019; Ulmschneider et al, 2016), melanocytes during zebrafish neural crest development (Raja et al, 2020), and mesoderm progenitors in the chicken embryo (Oginuma et al, 2020). Similar to our findings, an increasing pHi gradient is seen in murine colonic crypts (Amiri et al, 2021; Nikolovska et al, 2022), and reducing pHi is associated with decreased expression of absorptive fate genes (Nikolovska et al, 2022). Our study is distinct from these reports and adds to this growing area of investigation by identifying a role for pHi dynamics in lineage specification and providing a mechanistic understanding of pHi dynamics regulating ATOH1-dependent fate decision.…”

Section: Discussionsupporting

confidence: 90%

Intracellular pH dynamics regulates intestinal stem cell lineage specification

Liu

Reyes

Castillo-Azofeifa

et al. 2021

Preprint

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SummaryEmerging evidence is revealing critical roles of intracellular pH (pHi) in development (1–4), but it remains unclear whether pHi regulates stem cell fate specification. We find that pHi dynamics is a key regulator of cell fate in the mouse intestinal stem cell lineage. We identify a pHi gradient along the intestinal crypt axis and find that dissipating this gradient inhibits crypt budding due to loss Paneth cell differentiation. Mechanistically, decreasing pHi biases intestinal stem cell fate toward the absorptive and away from the secretory lineage, by regulating the activity of the lineage transcription factor Atoh1. Our findings reveal a previously unrecognized role for pHi dynamics in the specification of cell fate within an adult stem cell lineage.

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“…Since AE2 functions as a cellular acid loader, low AE2 activity will result in a high intracellular pH, as has been shown for intestinal crypt cells [ 36 ]. A high steady-state pH favors proliferation in malignant cells [ 59 ], as well as in intestinal nonmalignant cells [ 60 ]. A decrease in steady-state pH i as a consequence of the restoration of a Cl − efflux pathway by Slc26a9 overexpression in AGS cells and a concomitant upregulation of an endogenous HCO 3 − export pathway may be another mechanism explaining the increase in apoptosis and reduction in malignant behavior of AGS cells.…”

Section: Discussionmentioning

confidence: 99%

SLC26A9 deficiency causes gastric intraepithelial neoplasia in mice and aggressive gastric cancer in humans

Liu

et al. 2022

Cell Oncol.

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Background Solute carrier family 26 member (SLC26A9) is a Cl− uniporter with very high expression levels in the gastric mucosa. Here, we describe morphological and molecular alterations in gastric mucosa of slc26a9−/− mice and in selective parietal cell-deleted slc26a9fl/fl/Atp4b-Cre mice and correlate SLC26A9 expression levels with morphological and clinical parameters in a cohort of gastric cancer (GC) patients. Methods The expression patterns of genes related to transport and enzymatic function, proliferation, apoptosis, inflammation, barrier integrity, metaplasia and neoplasia development were studied by immunohistochemistry (IHC), quantitative RT-PCR, in situ hybridization and RNA microarray analysis. SLC26A9 expression and cellular/clinical phenotypes were studied in primary human GC tissues and GC cell lines. Results We found that both complete and parietal cell-selective Slc26a9 deletion in mice caused spontaneous development of gastric premalignant and malignant lesions. Dysregulated differentiation of gastric stem cells in an inflammatory environment, activated Wnt signaling, cellular hyperproliferation, apoptosis inhibition and metaplasia were observed. Analysis of human gastric precancerous and cancerous tissues revealed that SLC26A9 expression progressively decreased from atrophic gastritis to GC, and that downregulation of SLC26A9 was correlated with patient survival. Exogenous expression of SLC26A9 in GC cells induced upregulation of the Cl−/HCO3− exchanger AE2, G2/M cell cycle arrest and apoptosis and suppressed their proliferation, migration and invasion. Conclusions Our data indicate that SLC26A9 deletion in parietal cells is sufficient to trigger gastric metaplasia and the development of neoplastic lesions. In addition, we found that SLC26A9 expression decreases during human gastric carcinogenesis, and that exogenous SLC26A9 expression in GC cells reduces their malignant behavior. Graphical abstract

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The Role of pHi in Intestinal Epithelial Proliferation–Transport Mechanisms, Regulatory Pathways, and Consequences

Cited by 5 publications

References 86 publications

Intracellular pH dynamics regulates intestinal stem cell lineage specification

Intracellular pH dynamics regulates intestinal stem cell lineage specification

Intracellular pH dynamics regulates intestinal stem cell lineage specification

SLC26A9 deficiency causes gastric intraepithelial neoplasia in mice and aggressive gastric cancer in humans

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