Cloning and Variation of Ground State Intestinal Stem Cells

Despite major advances with embryonic and induced pluripotent stem cells or lineage-committed, p63-expressing stem cells of stratified epithelia, we know less about the indigenous stem cells of the gastrointestinal tract, pancreas, liver, and other columnar epithelia which collectively resist cloning in their elemental states. Here we demonstrate the cloning of highly immature epithelial stem cells from defined regions of the human intestine and colon. We show that single cell-derived pedigrees can be propagated indefinitely while often sustaining minimal copy number and sequence variation. Despite prolonged cultivation, these pedigrees from disparate regions of the intestinal tract respond to identical differentiation signals by formation of epithelia with eponymous structural and gene expression features. These data suggest developmental patterning of cell-autonomous commitment programs in stem cells that enforce specialization along the gastrointestinal tract and predict the utility of these cells in disease modeling and regenerative medicine. Stem cell clones and air-liquid interface of the stem cells from 6 parts of human fetal intestine