Fordham, Robert P3; Yui, Shiro5; Hannan, Nicholas R F4; Soendergaard, Christoffer4; Madgwick, Alison4; Schweiger, Pawel J5; Nielsen, Ole H6; Vallier, Ludovic4; Pedersen, Roger A4; Nakamura, Tetsuya4; Watanabe, Mamoru4; Jensen, Kim B5
1 Jensen Group, BRIC Research Groups, BRIC, Københavns Universitet2 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet3 Wellcome Trust & Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, CB2 1QR, UK; Anne McLaren Laboratory for Regenerative Medicine, Department of Surgery, University of Cambridge, Cambridge, CB2 0SZ, UK.4 unknown5 Jensen Group, BRIC Research Groups, BRIC, Københavns Universitet6 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet
Regeneration and homeostasis in the adult intestinal epithelium is driven by proliferative resident stem cells, whose functional properties during organismal development are largely unknown. Here, we show that human and mouse fetal intestine contains proliferative, immature progenitors, which can be expanded in vitro as Fetal Enterospheres (FEnS). A highly similar progenitor population can be established during intestinal differentiation of human induced pluripotent stem cells. Established cultures of mouse fetal intestinal progenitors express lower levels of Lgr5 than mature progenitors and propagate in the presence of the Wnt antagonist Dkk1, and new cultures can be induced to form mature intestinal organoids by exposure to Wnt3a. Following transplantation in a colonic injury model, FEnS contribute to regeneration of colonic epithelium by forming epithelial crypt-like structures expressing region-specific differentiation markers. This work provides insight into mechanisms underlying development of the mammalian intestine and points to future opportunities for patient-specific regeneration of the digestive tract.