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

Robert P Fordham,Shiro Yui,Nicholas R.F Hannan,Christoffer Soendergaard,Alison Madgwick,Pawel J Schweiger,Ole H Nielsen,Ludovic Vallier,Roger A Pedersen,Tetsuya Nakamura,Mamoru Watanabe,Kim B Jensen

doi:10.1016/j.stem.2013.09.015

Abstract

SummaryRegeneration 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.

Highlights

Fertilization of the oocyte initiates a series of events that, following gastrulation, leads to organ formation in the developing fetus
Regeneration and homeostasis in the adult intestinal epithelium is driven by proliferative resident stem cells, whose functional properties during organismal development are largely unknown
A highly similar progenitor population can be established during intestinal differentiation of human induced pluripotent stem cells

Summary

Introduction

Fertilization of the oocyte initiates a series of events that, following gastrulation, leads to organ formation in the developing fetus During this process, pluripotent stem cells progressively lose potential as the early embryo is patterned along its axes and organ structures are specified. Tissue-specific programs subsequently direct the formation and maturation of adult organs, which are maintained throughout life by stem cells with tissue-restricted lineage potential. Crypt formation occurs before birth, whereas in the mouse this happens during the first 2 postnatal weeks (Montgomery et al, 1999; Spence et al, 2011a) Beyond these morphological rearrangements, the mechanisms of initial intestinal lineage differentiation and functional maturation are less well characterized. Despite temporal differences in the ontogeny of the small intestine between human and mouse, the overall process of development is identical, making the mouse an accessible model to interrogate the process of human intestinal maturation

Results

Discussion

Conclusion