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. 2022 Mar;234(3):e13774.
doi: 10.1111/apha.13774. Epub 2022 Jan 21.

Sodium/hydrogen-exchanger-2 modulates colonocyte lineage differentiation

Katerina Nikolovska  1 , Li Cao  1   2 , Inga Hensel  1 , Gabriella Di Stefano  1 , Anna Elisabeth Seidler  1 , Kunyan Zhou  1 , Jiajie Qian  1   3 , Anurag Kumar Singh  1   4 , Brigitte Riederer  1 , Ursula Seidler  1
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Sodium/hydrogen-exchanger-2 modulates colonocyte lineage differentiation

Katerina Nikolovska et al. Acta Physiol (Oxf). 2022 Mar.

Abstract

Aim: The sodium/hydrogen exchanger 2 (NHE2) is an intestinal acid extruder with crypt-predominant localization and unresolved physiological significance. Our aim was to decipher its role in colonic epithelial cell proliferation, differentiation and electrolyte transport.

Methods: Alterations induced by NHE2-deficiency were addressed in murine nhe2-/- and nhe2+/+ colonic crypts and colonoids, and NHE2-knockdown and control Caco2Bbe cells using pH-fluorometry, gene expression analysis and immunofluorescence.

Results: pHi -measurements along the colonic cryptal axis revealed significantly decreased intracellular pH (pHi ) in the middle segment of nhe2-/- compared to nhe2+/+ crypts. Increased Nhe2 mRNA expression was detected in murine colonoids in the transiently amplifying/progenitor cell stage (TA/PE). Lack of Nhe2 altered the differentiation programme of colonic epithelial cells with reduced expression of absorptive lineage markers alkaline phosphatase (iAlp), Slc26a3 and transcription factor hairy and enhancer-of-split 1 (Hes1), but increased expression of secretory lineage markers Mucin 2, trefoil factor 3 (Tff3), enteroendocrine marker chromogranin A and murine atonal homolog 1 (Math1). Enterocyte differentiation was found to be pHi dependent with acidic pHi reducing, and alkaline pHi stimulating the expression of enterocyte differentiation markers in Caco2Bbe cells. A thicker mucus layer, longer crypts and an expanded brush border membrane zone of sodium/hydrogen exchanger 3 (NHE3) abundance may explain the lack of inflammation and the normal fluid absorptive rate in nhe2-/- colon.

Conclusions: The results suggest that NHE2 expression is activated when colonocytes emerge from the stem cell niche. Its activity increases progenitor cell pHi and thereby supports absorptive enterocyte differentiation.

Keywords: NHE2; colonoids; intestinal differentiation; intestinal electrolyte transport; pHi regulation; sodium/hydrogen exchange.

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References

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