Spatiotemporal reprogramming of differentiated cells underlies regeneration and neoplasia in the intestinal epithelium

Tsunaki Higa, Yasutaka Okita, Akinobu Matsumoto, Shogo Nakayama, Takeru Oka, Osamu Sugahara, Daisuke Koga, Shoichiro Takeishi, Hirokazu Nakatsumi, Naoki Hosen, Sylvie Robine, Makoto M. Taketo, Toshiro Sato and Keiichi I. Nakayama ()
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Tsunaki Higa: Medical Institute of Bioregulation, Kyushu University
Yasutaka Okita: Medical Institute of Bioregulation, Kyushu University
Akinobu Matsumoto: Medical Institute of Bioregulation, Kyushu University
Shogo Nakayama: Medical Institute of Bioregulation, Kyushu University
Takeru Oka: Medical Institute of Bioregulation, Kyushu University
Osamu Sugahara: Medical Institute of Bioregulation, Kyushu University
Daisuke Koga: Medical Institute of Bioregulation, Kyushu University
Shoichiro Takeishi: Medical Institute of Bioregulation, Kyushu University
Hirokazu Nakatsumi: Medical Institute of Bioregulation, Kyushu University
Naoki Hosen: Osaka University Graduate School of Medicine, Suita
Sylvie Robine: UMR 144, Institut Curie, 75248 Paris Cedex 05
Makoto M. Taketo: Graduate School of Medicine, Kyoto University
Toshiro Sato: Keio University School of Medicine
Keiichi I. Nakayama: Medical Institute of Bioregulation, Kyushu University

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Although the mammalian intestinal epithelium manifests robust regenerative capacity after various cytotoxic injuries, the underlying mechanism has remained unclear. Here we identify the cyclin-dependent kinase inhibitor p57 as a specific marker for a quiescent cell population located around the +4 position of intestinal crypts. Lineage tracing reveals that the p57+ cells serve as enteroendocrine/tuft cell precursors under normal conditions but dedifferentiate and act as facultative stem cells to support regeneration after injury. Single-cell transcriptomics analysis shows that the p57+ cells undergo a dynamic reprogramming process after injury that is characterized by fetal-like conversion and metaplasia-like transformation. Population-level analysis also detects such spatiotemporal reprogramming widely in other differentiated cell types. In intestinal adenoma, p57+ cells manifest homeostatic stem cell activity, in the context of constitutively activated spatiotemporal reprogramming. Our results highlight a pronounced plasticity of the intestinal epithelium that supports maintenance of tissue integrity in normal and neoplastic contexts.

Date: 2022
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DOI: 10.1038/s41467-022-29165-z

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