Transplantation of Expanded Fetal Intestinal Progenitors Contributes to Colon Regeneration after Injury

TLDR

Adult intestinal epithelium regeneration relies on resident stem cells, yet their functional properties during development remain largely unknown. The study seeks to uncover developmental mechanisms of the mammalian intestine and assess the potential for patient‑specific regenerative therapies. Human and mouse fetal intestines harbor proliferative immature progenitors that can be expanded as fetal enterospheres, mature with Wnt3a, and when transplanted into injured colon, form crypt‑like structures expressing region‑specific markers, demonstrating their regenerative capacity.

Abstract

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.