Z Gastroenterol 2020; 58(08): e145
DOI: 10.1055/s-0040-1716122
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Plasticity in adult Dclk1+ intestinal neuronal and glial cells facilitates regeneration and ganglionic cellular homeostasis

M Middelhoff
1   Klinikum rechts der Isar, Technische Universität München, Klinik und Poliklinik für Innere Medizin II, München, Deutschland
,
G Valenti
2   Columbia University, Digestive and Liver Diseases, New York, Vereinigte Staaten von Amerika
,
L Tomassoni
3   Columbia University, Department of Systems Biology, New York, Vereinigte Staaten von Amerika
,
P Laise
3   Columbia University, Department of Systems Biology, New York, Vereinigte Staaten von Amerika
,
R Takahashi
2   Columbia University, Digestive and Liver Diseases, New York, Vereinigte Staaten von Amerika
,
H Nienhüser
4   Universität Heidelberg, Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Heidelberg, Deutschland
,
M Finlayson
3   Columbia University, Department of Systems Biology, New York, Vereinigte Staaten von Amerika
,
B Belin
2   Columbia University, Digestive and Liver Diseases, New York, Vereinigte Staaten von Amerika
,
B Renz
5   LMU Klinikum, Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, München, Deutschland
,
B Westphalen
6   LMU Klinikum, Medizinische Klinik und Poliklinik III, München, Deutschland
,
M Quante
1   Klinikum rechts der Isar, Technische Universität München, Klinik und Poliklinik für Innere Medizin II, München, Deutschland
,
P Sims
3   Columbia University, Department of Systems Biology, New York, Vereinigte Staaten von Amerika
,
A Califano
3   Columbia University, Department of Systems Biology, New York, Vereinigte Staaten von Amerika
,
M Rao
7   Boston Children´s Hospital, Division of Gastroenterology, Hepatology and Nutrition, Boston, Vereinigte Staaten von Amerika
,
M Gershon
8   Columbia University, Department of Pathology and Cell Biology, New York, Vereinigte Staaten von Amerika
,
T Wang
2   Columbia University, Digestive and Liver Diseases, New York, Vereinigte Staaten von Amerika
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Background and aims Dclk1 is a kinase expressed in neural progenitor cells during murine neuronal development. Its reported presence in adult enteric ganglia suggests it may label cells with a similar degree of cellular plasticity. Hence, we aimed to elucidate the cellular identity of adult ganglionic Dclk1+ cells and their response to acute injury and increased serotonergic signaling.

Methods Myenteric Dclk1+ cells were identified by immunostaining with inverted or confocal microscopy. Dclk1-CreERT2 mice were employed for lineage tracing and genetic ablation studies. Whole body irradiation was employed as an acute injury model. Flow cytometry analysis using cd49b antibody staining facilitated single cell sorting and RNA sequencing of adult Dclk1+ ganglionic cells. SSRI treatment (Fluoxetine) was employed to increase serotonergic signaling.

Results During murine gut development, Dclk1 labels p75NTR-positive migrating neural crest cells and entirely traces enteric ganglia. The adult ganglionic Dclk1 lineage is heterogeneous, and stainings with the cell surface marker cd49b facilitated its separation into Dclk1+/nNOS+ and Dclk1+/Calb+ neurons next to Dclk1+/s100b+ and Dclk1+/Fapb7+ glia. Interestingly, Dclk1+ neurons and glia resist acute irradiation injury. Single-cell RNAseq analysis revealed that in response to acute injury Dclk1+ neurons upregulated ganglionic metabolism, while Dclk1+ glia upregulated neuro-immune crosstalk in a putative 5HTR3a-dependent manner. This response appears essential to govern ganglionic regeneration, as simultaneous genetic ablation of the Dclk1 lineage confers ganglionic cell loss. Increased serotonergic tone, however, revealed proliferative potential in Dclk1+/s100b+ glial and Dclk1+/Calb+ neuronal cells, thus evidencing a possible dual role of serotonergic agonism on Dclk1+ ganglionic cells.

Conclusion Dclk1 labels progenitor cells of the murine developing enteric nervous system. Adult Dclk1+ ganglionic cells are heterogeneous and committed to neuronal and glial differentiation, and appear essential for ganglionic regeneration. In addition, increased serotonergic signaling revealed proliferative potential in Dclk1+ glia and neurons, thus revealing a hitherto unprecedented cellular plasticity in adult enteric ganglia.



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08. September 2020

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