Nkx2.2 is expressed in a subset of enteroendocrine cells with expanded lineage potential

Am J Physiol Gastrointest Liver Physiol. 2015 Dec 15;309(12):G975-87. doi: 10.1152/ajpgi.00244.2015. Epub 2015 Oct 22.


There are two major stem cell populations in the intestinal crypt region that express either Bmi1 or Lgr5; however, it has been shown that other populations in the crypt can regain stemness. In this study, we demonstrate that the transcription factor NK2 homeobox 2 (Nkx2.2) is expressed in enteroendocrine cells located in the villus and crypt of the intestinal epithelium and is coexpressed with the stem cell markers Bmi1 and Lgr5 in a subset of crypt cells. To determine whether Nkx2.2-expressing enteroendocrine cells display cellular plasticity and stem cell potential, we performed genetic lineage tracing of the Nkx2.2-expressing population using Nkx2.2(Cre/+);R26RTomato mice. These studies demonstrated that Nkx2.2+ cells are able to give rise to all intestinal epithelial cell types in basal conditions. The proliferative capacity of Nkx2.2-expressing cells was also demonstrated in vitro using crypt organoid cultures. Injuring the intestine with irradiation, systemic inflammation, and colitis did not enhance the lineage potential of Nkx2.2-expressing cells. These findings demonstrate that a rare mature enteroendocrine cell subpopulation that is demarcated by Nkx2.2 expression display stem cell properties during normal intestinal epithelial homeostasis, but is not easily activated upon injury.

Keywords: Bmi1; Lgr5; Nkx2.2; enteroendocrine cells; stem cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Biomarkers / metabolism
  • Cell Differentiation*
  • Cell Lineage*
  • Cell Proliferation*
  • Cells, Cultured
  • Enteroendocrine Cells / metabolism*
  • Enteroendocrine Cells / pathology
  • Enteroendocrine Cells / radiation effects
  • Genotype
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Intestinal Mucosa / metabolism*
  • Intestinal Mucosa / pathology
  • Intestinal Mucosa / radiation effects
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nerve Tissue Proteins / metabolism
  • Phenotype
  • Pluripotent Stem Cells / metabolism*
  • Polycomb Repressive Complex 1 / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Receptors, G-Protein-Coupled / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Whole-Body Irradiation
  • Zebrafish Proteins


  • Basic Helix-Loop-Helix Transcription Factors
  • Biomarkers
  • Bmi1 protein, mouse
  • Homeodomain Proteins
  • Lgr5 protein, mouse
  • Luminescent Proteins
  • Nerve Tissue Proteins
  • Neurog3 protein, mouse
  • Nkx2.2 protein
  • Proto-Oncogene Proteins
  • Receptors, G-Protein-Coupled
  • Transcription Factors
  • Zebrafish Proteins
  • red fluorescent protein
  • Polycomb Repressive Complex 1