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. 2024 Jun 6;187(12):3056-3071.e17.
doi: 10.1016/j.cell.2024.05.004.

Isthmus progenitor cells contribute to homeostatic cellular turnover and support regeneration following intestinal injury

Ermanno Malagola  1 , Alessandro Vasciaveo  2 , Yosuke Ochiai  1 , Woosook Kim  1 , Biyun Zheng  3 , Luca Zanella  2 , Alexander L E Wang  2 , Moritz Middelhoff  4 , Henrik Nienhüser  5 , Lu Deng  6 , Feijing Wu  1 , Quin T Waterbury  1 , Bryana Belin  1 , Jonathan LaBella  1 , Leah B Zamechek  1 , Melissa H Wong  7 , Linheng Li  6 , Chandan Guha  8 , Chia-Wei Cheng  9 , Kelley S Yan  10 , Andrea Califano  11 , Timothy C Wang  12
Affiliations

Isthmus progenitor cells contribute to homeostatic cellular turnover and support regeneration following intestinal injury

Ermanno Malagola et al. Cell. .

Abstract

The currently accepted intestinal epithelial cell organization model proposes that Lgr5+ crypt-base columnar (CBC) cells represent the sole intestinal stem cell (ISC) compartment. However, previous studies have indicated that Lgr5+ cells are dispensable for intestinal regeneration, leading to two major hypotheses: one favoring the presence of a quiescent reserve ISC and the other calling for differentiated cell plasticity. To investigate these possibilities, we studied crypt epithelial cells in an unbiased fashion via high-resolution single-cell profiling. These studies, combined with in vivo lineage tracing, show that Lgr5 is not a specific ISC marker and that stemness potential exists beyond the crypt base and resides in the isthmus region, where undifferentiated cells participate in intestinal homeostasis and regeneration following irradiation (IR) injury. Our results provide an alternative model of intestinal epithelial cell organization, suggesting that stemness potential is not restricted to CBC cells, and neither de-differentiation nor reserve ISC are drivers of intestinal regeneration.

Keywords: adult stem cells; cell potency; epithelial stem cells; intestinal stem cells; intestine; plasticity; regeneration; regulatory network analysis; single cell; stemness signature.

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Conflict of interest statement

Declaration of interests Dr. A.C. is the founder, equity holder, and consultant of DarwinHealth Inc., a company that has licensed some of the algorithms used in this manuscript from Columbia University. Columbia University is also an equity holder in DarwinHealth Inc.

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