TY - JOUR
T1 - Spatiotemporal reprogramming of differentiated cells underlies regeneration and neoplasia in the intestinal epithelium
AU - Higa, Tsunaki
AU - Okita, Yasutaka
AU - Matsumoto, Akinobu
AU - Nakayama, Shogo
AU - Oka, Takeru
AU - Sugahara, Osamu
AU - Koga, Daisuke
AU - Takeishi, Shoichiro
AU - Nakatsumi, Hirokazu
AU - Hosen, Naoki
AU - Robine, Sylvie
AU - Taketo, Makoto M.
AU - Sato, Toshiro
AU - Nakayama, Keiichi I.
N1 - Funding Information:
We thank F. de Sauvage (Genentech Inc.) for providing Lgr5-DTR-EGFP transgenic mice, Y. Ohkawa (Medical Institute of Bioregulation, Kyushu University) for discussion on scRNA-seq experiments, M. Ikawa (Research Institute for Microbial Diseases, Osaka, Japan) for discussion on generation of knock-in mice, as well as A. Niihara, H. Takayoshi, M. Tanaka, and K. Nagatoshi for technical assistance. This work was supported in part by KAKENHI grants from Japan Society for the Promotion of Science (JSPS) and the Ministry of Education, Culture, Sports, Science, and Technology of Japan to K.I.N. (JP18H05215) and to T.H. (JP19K16716) as well as by the Project for Cancer Research and Therapeutic Evolution (P-CREATE) of the Japan Agency for Medical Research and Development (AMED) to K.I.N. (JP21cm0106105).
Funding Information:
We thank F. de Sauvage (Genentech Inc.) for providing Lgr5-DTR-EGFP transgenic mice, Y. Ohkawa (Medical Institute of Bioregulation, Kyushu University) for discussion on scRNA-seq experiments, M. Ikawa (Research Institute for Microbial Diseases, Osaka, Japan) for discussion on generation of knock-in mice, as well as A. Niihara, H. Takayoshi, M. Tanaka, and K. Nagatoshi for technical assistance. This work was supported in part by KAKENHI grants from Japan Society for the Promotion of Science (JSPS) and the Ministry of Education, Culture, Sports, Science, and Technology of Japan to K.I.N. (JP18H05215) and to T.H. (JP19K16716) as well as by the Project for Cancer Research and Therapeutic Evolution (P-CREATE) of the Japan Agency for Medical Research and Development (AMED) to K.I.N. (JP21cm0106105).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85126783590&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-29165-z
DO - 10.1038/s41467-022-29165-z
M3 - Article
C2 - 35314700
AN - SCOPUS:85126783590
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1500
ER -