Nkx2.2 is expressed in a subset of enteroendocrine cells with expanded lineage potential.
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.
Department of Genetics and Development, Columbia University Medical Center, New York, New York;
Stefanie
S
Gross
Department of Genetics and Development, Columbia University Medical Center, New York, New York;
Dina
D
Balderes
Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee;
Jing
J
Liu
Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, New York; and.
Samuel
S
Asfaha
Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee;
Guoqiang
G
Gu
Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, New York; and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York.
Timothy C
TC
Wang
Department of Genetics and Development, Columbia University Medical Center, New York, New York; lgs2@columbia.edu.
Lori
L
Sussel
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002478:Cells, Cultured; D019858:Enteroendocrine Cells / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D005838:Genotype; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010641:Phenotype; D039904:Pluripotent Stem Cells / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014916:Whole-Body Irradiation; D029961:Zebrafish Proteins; D000097573:Red Fluorescent Protein
D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D014157:Transcription Factors; D029961:Zebrafish Proteins; D000097573:Red Fluorescent Protein; C489421:Bmi1 protein, mouse; C493597:Lgr5 protein, mouse; C407737:Neurog3 protein, mouse; C000715627:Nkx2-2 protein, mouse; C000715630:nkx2.2b protein, zebrafish
Bmi1; Lgr5; Nkx2.2; enteroendocrine cells; stem cells