Z Gastroenterol 2021; 59(08): e204-e205
DOI: 10.1055/s-0041-1733607
Grundlagenforschung Pankreas und Leber
Mittwoch, 15. September 2021, 12:00-13:20 Uhr, After-Work-Stream: Kanal 1
Neurogastroenterologie und Motilität

Vasoactive intestinal peptide modulates intestinal stem cell activity and differentiation

T Agibalova
1   Klinikum rechts der Isar der Technischen Universität München, München, Deutschland
,
J Wieland
1   Klinikum rechts der Isar der Technischen Universität München, München, Deutschland
,
IE Demir
1   Klinikum rechts der Isar der Technischen Universität München, München, Deutschland
,
D Saur
1   Klinikum rechts der Isar der Technischen Universität München, München, Deutschland
,
M Quante
1   Klinikum rechts der Isar der Technischen Universität München, München, Deutschland
2   Universitätsklinikum Freiburg, Freiburg, Deutschland
,
Schmid RM
1   Klinikum rechts der Isar der Technischen Universität München, München, Deutschland
,
M Middelhoff
1   Klinikum rechts der Isar der Technischen Universität München, München, Deutschland
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Introduction Vasoactive intestinal peptide (VIP) is a neuropeptide widely expressed in enteric myenteric and submucosal ganglia. VIP exerts important physiological functions, such as regulation of epithelial secretion and smooth muscle contraction, predominantly via its Gs-protein-coupled receptor VPAC1. VIP-KO mice show abnormal intestinal villus-crypt architecture, increased proliferation and reduced number of goblet cells, substantiating a crucial role for VIP in intestinal homeostasis. Transmitters, such as acetylcholine, prominently modulate intestinal stem cell (ISC) activity and differentiation, yet little is known about the specific effects of VIP on ISC in homeostasis.

Aims Determine the effect of VIP on ISC activity and differentiation.

Methods Intestinal VIP receptor expression was extracted from published single-cell data sets and confirmed by immunohistochemistry for VPAC1. In order to study the effect of VIP, intestinal jejunal organoids were derived from adult WT mice, treated with VIP and then analyzed by RT-PCR analysis, immunostainings and bulk RNA sequencing analysis. Current experiments include additional validation experiments, analysis of the effect of VIP treatments on Lgr5+ ISC and in vivo treatments.

Results VIP-treated organoids revealed a strong phenotypic switch to a more cystic appearance already 24h after the treatment onset. RT-PCR analysis confirmed the upregulation of secretory markers Lyz1 and Muc2 in VIP-treated organoids, which translated into increased numbers of Lyz1-positive Paneth and Muc2-positive goblet cells, as revealed by immunostainings. Principal component analysis of bulk RNA sequencing data confirmed a clear separation of organoids by VIP treatment. Further, VIP treatment induced a strong, significant upregulation of hallmark pathways for epithelial-mesenchymal transition, TNFa signaling via NF-kB and p53 pathway.

Conclusion The observed results indicate that VIP plays an important role in the modulation of stem cell activity by driving differentiation towards a secretory phenotype. Moreover, VIP triggers the upregulation of pathways linked to cellular survival and anti-apoptotic response demonstrating the significance of VIP during homeostasis and regeneration.



Publication History

Article published online:
07 September 2021

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