Contribution of ATOH1+ Cells to the Homeostasis, Repair, and Tumorigenesis of the Colonic Epithelium

Abstract

ATOH1 is a master transcription factor for the secretory lineage differentiation of intestinal epithelial cells (IECs). However, the comprehensive contribution of ATOH1⁺ secretory lineage IECs to the homeostasis, repair, and tumorigenesis of the intestinal epithelium remains uncertain. Through our ATOH1⁺ cell-lineage tracing, we show here that a definite number of ATOH1⁺ IECs retain stem cell properties and can form ATOH1⁺IEC-derived clonal ribbons (ATOH1⁺ICRs) under completely homeostatic conditions. Interestingly, colonic ATOH1⁺ IECs appeared to exhibit their stem cell function more frequently compared with those of the small intestine. Consistently, the formation of ATOH1⁺ICRs was significantly enhanced upon dextran sodium sulfate colitis-induced mucosal damage. In addition, colonic ATOH1⁺ IECs acquired tumor stem cell-like properties in the azoxymethane-DSS tumor model. Our results reveal an unexpected contribution of colonic ATOH1⁺ IECs to maintaining the stem cell population under both homeostatic and pathologic conditions and further illustrate the high plasticity of the crypt-intrinsic stem cell hierarchy.