Isthmus Progenitor Cells Contribute to Homeostatic Cellular Turnover and Support Regeneration Following Intestinal Injury

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2024 Jun 7

PMID 38848678

Authors

Ermanno Malagola

Alessandro Vasciaveo

Yosuke Ochiai

Woosook Kim

Biyun Zheng

Luca Zanella

Alexander L E Wang

Moritz Middelhoff

Henrik Nienhuser

Lu Deng

Feijing Wu

Quin T Waterbury

Bryana Belin

Jonathan LaBella

Leah B Zamechek

Melissa H Wong

Linheng Li

Chandan Guha

Chia-Wei Cheng

Kelley S Yan

Andrea Califano

Timothy C Wang

Affiliations

Soon will be listed here.

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.

Citing Articles

Establishment of a novel mouse model of colorectal cancer by orthotopic transplantation.

Chen C, Fu Q, Wang L, Tanaka S, Imajo M BMC Cancer. 2025; 25(1):405.

PMID: 40050746 PMC: 11884030. DOI: 10.1186/s12885-025-13834-5.

Prmt5 is essential for intestinal stem cell maintenance and homeostasis.

Yang L, Li X, Shi C, Zhao B Cell Regen. 2025; 14(1):5.

PMID: 39907873 PMC: 11799473. DOI: 10.1186/s13619-024-00216-8.

The E2F4 transcriptional repressor is a key mechanistic regulator of colon cancer resistance to (CPT-11).

Matsubara J, Li Y, Koul S, Mukohyama J, Salazar L, Isobe T bioRxiv. 2025; .

PMID: 39896677 PMC: 11785039. DOI: 10.1101/2025.01.22.633435.

Dynamic Reprogramming of Stromal Pdgfra-expressing cells during WNT-Mediated Transformation of the Intestinal Epithelium.

Pellon-Cardenas O, Rout P, Hassan S, Fokas E, Ping H, Patel I bioRxiv. 2025; .

PMID: 39896606 PMC: 11785226. DOI: 10.1101/2025.01.22.634326.

HMGA1 is a crucial mediator of colon tumorigenesis driven by the loss of APC.

Wang Y, Ybarra M, Wang Z J Clin Invest. 2025; 135(3).

PMID: 39895631 PMC: 11785912. DOI: 10.1172/JCI187442.

References

Montgomery R, Carlone D, Richmond C, Farilla L, Kranendonk M, Henderson D . Mouse telomerase reverse transcriptase (mTert) expression marks slowly cycling intestinal stem cells. Proc Natl Acad Sci U S A. 2010; 108(1):179-84. PMC: 3017192. DOI: 10.1073/pnas.1013004108. View

Granja J, Corces M, Pierce S, Bagdatli S, Choudhry H, Chang H . ArchR is a scalable software package for integrative single-cell chromatin accessibility analysis. Nat Genet. 2021; 53(3):403-411. PMC: 8012210. DOI: 10.1038/s41588-021-00790-6. View

Sato T, Vries R, Snippert H, van de Wetering M, Barker N, Stange D . Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature. 2009; 459(7244):262-5. DOI: 10.1038/nature07935. View

Tan S, Phuah P, Tan L, Yada S, Goh J, Tomaz L . A constant pool of Lgr5 intestinal stem cells is required for intestinal homeostasis. Cell Rep. 2021; 34(4):108633. DOI: 10.1016/j.celrep.2020.108633. View

Yui S, Azzolin L, Maimets M, Pedersen M, Fordham R, Hansen S . YAP/TAZ-Dependent Reprogramming of Colonic Epithelium Links ECM Remodeling to Tissue Regeneration. Cell Stem Cell. 2017; 22(1):35-49.e7. PMC: 5766831. DOI: 10.1016/j.stem.2017.11.001. View

Bezencon C, Furholz A, Raymond F, Mansourian R, Metairon S, le Coutre J . Murine intestinal cells expressing Trpm5 are mostly brush cells and express markers of neuronal and inflammatory cells. J Comp Neurol. 2008; 509(5):514-25. DOI: 10.1002/cne.21768. View

Hayakawa Y, Nakagawa H, Rustgi A, Que J, Wang T . Stem cells and origins of cancer in the upper gastrointestinal tract. Cell Stem Cell. 2021; 28(8):1343-1361. PMC: 8844710. DOI: 10.1016/j.stem.2021.05.012. View

Percharde M, Lin C, Yin Y, Guan J, Peixoto G, Bulut-Karslioglu A . A LINE1-Nucleolin Partnership Regulates Early Development and ESC Identity. Cell. 2018; 174(2):391-405.e19. PMC: 6046266. DOI: 10.1016/j.cell.2018.05.043. View

Oppikofer M, Sagolla M, Haley B, Zhang H, Kummerfeld S, Sudhamsu J . Non-canonical reader modules of BAZ1A promote recovery from DNA damage. Nat Commun. 2017; 8(1):862. PMC: 5636791. DOI: 10.1038/s41467-017-00866-0. View

10.

Leushacke M, Tan S, Wong A, Swathi Y, Hajamohideen A, Tan L . Lgr5-expressing chief cells drive epithelial regeneration and cancer in the oxyntic stomach. Nat Cell Biol. 2017; 19(7):774-786. DOI: 10.1038/ncb3541. View

11.

Yu T, Cazares O, Tang A, Kim H, Wald T, Verma A . SRSF1 governs progenitor-specific alternative splicing to maintain adult epithelial tissue homeostasis and renewal. Dev Cell. 2022; 57(5):624-637.e4. PMC: 8974236. DOI: 10.1016/j.devcel.2022.01.011. View

12.

van der Flier L, van Gijn M, Hatzis P, Kujala P, Haegebarth A, Stange D . Transcription factor achaete scute-like 2 controls intestinal stem cell fate. Cell. 2009; 136(5):903-12. DOI: 10.1016/j.cell.2009.01.031. View

13.

Bottcher A, Buttner M, Tritschler S, Sterr M, Aliluev A, Oppenlander L . Non-canonical Wnt/PCP signalling regulates intestinal stem cell lineage priming towards enteroendocrine and Paneth cell fates. Nat Cell Biol. 2021; 23(1):23-31. DOI: 10.1038/s41556-020-00617-2. View

14.

Sheng X, Lin Z, Lv C, Shao C, Bi X, Deng M . Cycling Stem Cells Are Radioresistant and Regenerate the Intestine. Cell Rep. 2020; 32(4):107952. PMC: 7789978. DOI: 10.1016/j.celrep.2020.107952. View

15.

Margolin A, Nemenman I, Basso K, Wiggins C, Stolovitzky G, Dalla Favera R . ARACNE: an algorithm for the reconstruction of gene regulatory networks in a mammalian cellular context. BMC Bioinformatics. 2006; 7 Suppl 1:S7. PMC: 1810318. DOI: 10.1186/1471-2105-7-S1-S7. View

16.

Ayyaz A, Kumar S, Sangiorgi B, Ghoshal B, Gosio J, Ouladan S . Single-cell transcriptomes of the regenerating intestine reveal a revival stem cell. Nature. 2019; 569(7754):121-125. DOI: 10.1038/s41586-019-1154-y. View

17.

Alvarez M, Shen Y, Giorgi F, Lachmann A, Ding B, Ye B . Functional characterization of somatic mutations in cancer using network-based inference of protein activity. Nat Genet. 2016; 48(8):838-47. PMC: 5040167. DOI: 10.1038/ng.3593. View

18.

van Es J, Sato T, van de Wetering M, Lyubimova A, Yee Nee A, Gregorieff A . Dll1+ secretory progenitor cells revert to stem cells upon crypt damage. Nat Cell Biol. 2012; 14(10):1099-1104. PMC: 3789123. DOI: 10.1038/ncb2581. View

19.

Mull A, Klar A, Navara C . Differential localization and high expression of SURVIVIN splice variants in human embryonic stem cells but not in differentiated cells implicate a role for SURVIVIN in pluripotency. Stem Cell Res. 2014; 12(2):539-49. DOI: 10.1016/j.scr.2014.01.002. View

20.

Beumer J, Clevers H . Cell fate specification and differentiation in the adult mammalian intestine. Nat Rev Mol Cell Biol. 2020; 22(1):39-53. DOI: 10.1038/s41580-020-0278-0. View