Activation of fetal-like molecular programs during regeneration in the intestine and beyond

doi:10.1016/j.stem.2024.05.009

Review

. 2024 Jul 5;31(7):949-960.

doi: 10.1016/j.stem.2024.05.009.

Activation of fetal-like molecular programs during regeneration in the intestine and beyond

Sara Viragova¹, Dong Li², Ophir D Klein³

Affiliations

¹ Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, San Francisco, CA, USA.
² Department of Pediatrics, Cedars-Sinai Guerin Children's, Los Angeles, CA, USA.
³ Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, San Francisco, CA, USA; Department of Pediatrics, Cedars-Sinai Guerin Children's, Los Angeles, CA, USA. Electronic address: ophir.klein@cshs.org.

PMID: 38971147
PMCID: PMC11235077 (available on 2025-07-05)
DOI: 10.1016/j.stem.2024.05.009

Review

Activation of fetal-like molecular programs during regeneration in the intestine and beyond

Sara Viragova et al. Cell Stem Cell. 2024.

. 2024 Jul 5;31(7):949-960.

doi: 10.1016/j.stem.2024.05.009.

Authors

Sara Viragova¹, Dong Li², Ophir D Klein³

Affiliations

¹ Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, San Francisco, CA, USA.
² Department of Pediatrics, Cedars-Sinai Guerin Children's, Los Angeles, CA, USA.
³ Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, San Francisco, CA, USA; Department of Pediatrics, Cedars-Sinai Guerin Children's, Los Angeles, CA, USA. Electronic address: ophir.klein@cshs.org.

PMID: 38971147
PMCID: PMC11235077 (available on 2025-07-05)
DOI: 10.1016/j.stem.2024.05.009

Abstract

Tissue regeneration after damage is generally thought to involve the mobilization of adult stem cells that divide and differentiate into progressively specialized progeny. However, recent studies indicate that tissue regeneration can be accompanied by reversion to a fetal-like state. During this process, cells at the injury site reactivate programs that operate during fetal development but are typically absent in adult homeostasis. Here, we summarize our current understanding of the molecular signals and epigenetic mediators that orchestrate "fetal-like reversion" during intestinal regeneration. We also explore evidence for this phenomenon in other organs and species and highlight open questions that merit future examination.

Keywords: Hippo; YAP; colon; dedifferentiation; developmental reprogramming; epithelium; fetal-like reversion; intestinal epithelium; intestine; liver; paligenosis; plasticity; regeneration; stem cells; stomach.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

References

1. Gehart H, and Clevers H (2019). Tales from the crypt: new insights into intestinal stem cells. Nat Rev Gastroenterol Hepatol 16, 19–34. 10.1038/s41575-018-0081-y. - DOI - PubMed
1. Zwick RK, Kasparek P, Palikuqi B, Viragova S, Weichselbaum L, McGinnis CS, McKinley KL, Rathnayake A, Vaka D, Nguyen V, et al. (2024). Epithelial zonation along the mouse and human small intestine defines five discrete metabolic domains. Nat Cell Biol 26, 250–262. 10.1038/s41556-023-01337-z. - DOI - PubMed
1. Barker N, Van Es JH, Kuipers J, Kujala P, Van Den Born M, Cozijnsen M, Haegebarth A, Korving J, Begthel H, and Peters PJ (2007). Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007. - PubMed
1. Van der Flier LG, Haegebarth A, Stange DE, Van de Wetering M, and Clevers H (2009). OLFM4 is a robust marker for stem cells in human intestine and marks a subset of colorectal cancer cells. Gastroenterology 137, 15–17. - PubMed
1. Malagola E, Vasciaveo A, Ochiai Y, Kim W, Zheng B, Zanella L, Wang AL, Middelhoff M, Nienhüser H, and Deng L (2024). Isthmus progenitor cells contribute to homeostatic cellular turnover and support regeneration following intestinal injury. Cell 187, 3056–3071. e3017. - PMC - PubMed

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[1] Gehart H, and Clevers H (2019). Tales from the crypt: new insights into intestinal stem cells. Nat Rev Gastroenterol Hepatol 16, 19–34. 10.1038/s41575-018-0081-y. - DOI - PubMed

[2] Gehart H, and Clevers H (2019). Tales from the crypt: new insights into intestinal stem cells. Nat Rev Gastroenterol Hepatol 16, 19–34. 10.1038/s41575-018-0081-y. - DOI - PubMed

[3] Zwick RK, Kasparek P, Palikuqi B, Viragova S, Weichselbaum L, McGinnis CS, McKinley KL, Rathnayake A, Vaka D, Nguyen V, et al. (2024). Epithelial zonation along the mouse and human small intestine defines five discrete metabolic domains. Nat Cell Biol 26, 250–262. 10.1038/s41556-023-01337-z. - DOI - PubMed

[4] Zwick RK, Kasparek P, Palikuqi B, Viragova S, Weichselbaum L, McGinnis CS, McKinley KL, Rathnayake A, Vaka D, Nguyen V, et al. (2024). Epithelial zonation along the mouse and human small intestine defines five discrete metabolic domains. Nat Cell Biol 26, 250–262. 10.1038/s41556-023-01337-z. - DOI - PubMed

[5] Barker N, Van Es JH, Kuipers J, Kujala P, Van Den Born M, Cozijnsen M, Haegebarth A, Korving J, Begthel H, and Peters PJ (2007). Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007. - PubMed

[6] Barker N, Van Es JH, Kuipers J, Kujala P, Van Den Born M, Cozijnsen M, Haegebarth A, Korving J, Begthel H, and Peters PJ (2007). Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007. - PubMed

[7] Van der Flier LG, Haegebarth A, Stange DE, Van de Wetering M, and Clevers H (2009). OLFM4 is a robust marker for stem cells in human intestine and marks a subset of colorectal cancer cells. Gastroenterology 137, 15–17. - PubMed

[8] Van der Flier LG, Haegebarth A, Stange DE, Van de Wetering M, and Clevers H (2009). OLFM4 is a robust marker for stem cells in human intestine and marks a subset of colorectal cancer cells. Gastroenterology 137, 15–17. - PubMed

[9] Malagola E, Vasciaveo A, Ochiai Y, Kim W, Zheng B, Zanella L, Wang AL, Middelhoff M, Nienhüser H, and Deng L (2024). Isthmus progenitor cells contribute to homeostatic cellular turnover and support regeneration following intestinal injury. Cell 187, 3056–3071. e3017. - PMC - PubMed

[10] Malagola E, Vasciaveo A, Ochiai Y, Kim W, Zheng B, Zanella L, Wang AL, Middelhoff M, Nienhüser H, and Deng L (2024). Isthmus progenitor cells contribute to homeostatic cellular turnover and support regeneration following intestinal injury. Cell 187, 3056–3071. e3017. - PMC - PubMed

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Activation of fetal-like molecular programs during regeneration in the intestine and beyond

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Activation of fetal-like molecular programs during regeneration in the intestine and beyond

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