Adult enteric Dclk1-positive glial and neuronal cells reveal distinct responses to acute intestinal injury

Moritz Middelhoff, Giovanni Valenti, Lorenzo Tomassoni, Yosuke Ochiai, Bryana Belin, Ryota Takahashi, Ermanno Malagola, Henrik Nienhuser, Michael Finlayson, Yoku Hayakawa, Leah B. Zamechek, Bernhard W. Renz, C. Benedikt Westphalen, Michael Quante, Kara G. Margolis, Peter A. Sims, Pasquale Laise, Andrea Califano, Meenakshi Rao, Michael D. GershonTimothy C. Wang

Research output: Contribution to journalArticlepeer-review


Intestinal ganglionic cells in the adult enteric nervous system (ENS) are continually exposed to stimuli from the surrounding microenvironment and need at times to respond to disturbed homeostasis following acute intestinal injury. The kinase DCLK1 and intestinal Dclk1-positive cells have been reported to contribute to intestinal regeneration. Although Dclk1-positive cells are present in adult enteric ganglia, their cellular identity and response to acute injury have not been investigated in detail. Here, we reveal the presence of distinct Dclk1-tdTom þ/CD49b þ glial-like and Dclk1-tdTom þ/CD49b- neuronal cell types in adult myenteric ganglia. These ganglionic cells demonstrate distinct patterns of tracing over time yet show a similar expansion in response to elevated serotonergic signaling. Interestingly, Dclk1-tdTom þ glial-like and neuronal cell types appear resistant to acute irradiation injury-mediated cell death. Moreover, Dclk1-tdTom þ/CD49b þ glial-like cells show prominent changes in gene expression profiles induced by injury, in contrast to Dclk1-tdTom þ/CD49b- neuronal cell types. Finally, subsets of Dclk1-tdTom þ/CD49b þ glial-like cells demonstrate prominent overlap with Nestin and p75NTR and strong responses to elevated serotonergic signaling or acute injury. These findings, together with their role in early development and their neural crest-like gene expression signature, suggest the presence of reserve progenitor cells in the adult Dclk1 glial cell lineage. NEW & NOTEWORTHY The kinase DCLK1 identifies glial-like and neuronal cell types in adult murine enteric ganglia, which resist acute injury-mediated cell death yet differ in their cellular response to injury. Interestingly, Dclk1-labeled glial-like cells show prominent transcriptional changes in response to injury and harbor features reminiscent of previously described enteric neural precursor cells. Our data thus add to recently emerging evidence of reserve cellular plasticity in the adult enteric nervous system.

Original languageEnglish (US)
Pages (from-to)G583-G597
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Issue number6
StatePublished - 2022


  • Dclk1
  • enteric nervous system
  • ganglionic homeostasis and regeneration
  • reserve ganglionic progenitor cells

ASJC Scopus subject areas

  • General Medicine


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