Friedrich Miescher Institute for Biomedical Research, Basel-Stadt, Switzerland
The human intestinal epithelium is a tissue with rapid turnover. The complexity of its regenerative process and differentiation trajectories has been challenging to study due to its inaccessibility and lack of temporal sampling. To this end, we developed a workflow to culture biopsy-derived human intestinal organoids from single cells until maturation. Extensive characterization indicated a transient regenerative response in our model system, followed by differentiation into all mature cell lineages. This switch is accompanied by a transition between two stem cell states. High content-screening and comparison to in vivo studies revealed that an initial fetal-like state is crucial for achieving successful regeneration, while the subsequent adult-like state is vital for maintaining a proper balance of cell lineages and crypt-morphogenesis. Taken together, this study highlights the extensive plasticity of the intestinal epithelium and paves the way for further studies of human intestinal regeneration and its deregulation in pathologies.