Advanced Progression for the Heterogeneity and Homeostasis of Intestinal Stem Cells

Current understanding of the leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) in intestinal stem cells (ISCs) is well established, however, the implications of ISC heterogeneity and homeostasis are poorly understood. Prior studies have provided important evidence for the association between heterogeneity of ISC pools with pathogenesis and therapeutic response of malignant disease. Leveraging the advantages of organoids and single cell RNA sequencing (scRNA-seq), glandular development has been simulated and cell heterogeneity has been clarified. Based on this research, several potential ISCs were identified, such as LGR5 + p27 + quiescent ISCs, LGR5 + Mex3a + slowly proliferating stem cells, and CLU + reverse stem cells. We also illustrated major factors responsible for ISC homeostasis including metabolism-related (LKB1, TGR5, HMGCS2), inflammation-related (IFB-b, IFN2, TNF), and Wnt signaling-related (CREPT, Mex3a, MTG16) factors. ISCs play complex roles in intestinal tumorigenesis, chemoresistance and occasional relapse of colon cancer, which bear discussion. In this review, we focus on novel technical challenges in ISCs fate drawing upon recent research with the goals of clarifying our understanding of complex ISCs, elucidating the integrated intestinal crypt niche, and creating new opportunities for therapeutic development.