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Embryonic Origin Dictates Functional Heterogeneity and Neoplastic Potential in Adult Intestinal Stem Cells [scRNA-seq_adult_SI_crypts]

ABSTRACT: Adult intestinal stem cells (ISCs) are the primary source of all differentiated cell types within the intestine and also the cells-of-origin of intestinal cancer. Traditionally, ISCs were viewed as a functionally uniform population. Here, we show that ISCs derived from Axin2+ embryonic progenitors are a functionally distinct group. During homeostasis, Axin2+-derived ISCs exhibit an increased capacity to differentiate into tuft and enteroendocrine cells, but are markedly less efficient at generating Paneth cells. Mechanistically, ISC differentiation potential is established during embryogenesis and shaped by a combination of cell-intrinsic factors, including WNT signaling and transcriptional regulators, as well as external BMP cues from the surrounding microenvironment. Consequently, the differentiation potential of adult ISCs into secretory lineages can be altered by temporary suppression of BMP signalling during embryonic development. We further demonstrate that Axin2+-derived ISCs display a higher propensity for neoplastic transformation in the Apcmin/+ mouse model for intestinal cancer. Moreover, a marker of Axin2+-derived epithelial cells, CSRNP3 is overexpressed in the inflamed and cancerous epithelium of patients with IBD and colorectal cancer. Our study reveals the cell-intrinsic nature of ISC differentiation potential, defined during embryogenesis, and underscores the importance of embryonic signaling cues in determining the functional outcomes of adult ISCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE277651 | GEO | 2026/03/09

REPOSITORIES: GEO

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