Generation of Mouse and Human Organoid-Forming Intestinal Progenitor Cells by Direct Lineage Reprogramming

摘要

Summary Intestinal organoids hold great promise as a valuable tool for studying and treating intestinal diseases. The currently available sources of human intestinal organoids, tissue fragments or pluripotent stem cells, involve invasive procedures or complex differentiation protocols, respectively. Here, we show that a set of four transcription factors, Hnf4α, Foxa3, Gata6, and Cdx2, can directly reprogram mouse fibroblasts to acquire the identity of fetal intestine-derived progenitor cells (FIPCs). These induced FIPCs (iFIPCs) form spherical organoids that develop into adult-type budding organoids containing cells with intestinal stem cell properties. The resulting stem cells produce all intestinal epithelial cell lineages and undergo self-renewing cell divisions. After transplantation, the induced spherical and budding organoids can reconstitute colonic and intestinal epithelia, respectively. The same combination of four defined transcription factors can also induce human iFIPCs. This alternative approach for producing intestinal organoids may well facilitate application for disease analysis and therapy development. Graphical Abstract Display Omitted Highlights ? Direct lineage reprogramming can induce fetal intestinal progenitor cells (iFIPCs) ? Mouse and human iFIPCs are expandable and form spherical organoids in culture ? Mouse iFIPC-derived spherical organoids develop into adult-type budding organoids ? Mouse and human iFIPCs regenerate colonic epithelial tissues after transplantation Miura and Suzuki describe direct conversion of mouse fibroblasts to cells resembling fetal intestine-derived progenitor cells that can give rise to intestinal stem cell organoids and reconstitute injured colonic tissues after transplantation. They also show that a similar approach can work to make human induced intestinal progenitor cells.