Wednesday, July 29, 2026
No menu items!
HomeNatureIntestinal stem cells count self-renewal divisions to switch multipotency

Intestinal stem cells count self-renewal divisions to switch multipotency

  • Carrelha, J. et al. Hierarchically related lineage-restricted fates of multipotent haematopoietic stem cells. Nature 554, 106–111 (2018).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Banjac, I. et al. Fate mapping in mouse demonstrates early secretory differentiation directly from Lgr5+ intestinal stem cells. Dev. Cell 60, 1281–1289 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ohlstein, B. & Spradling, A. The adult Drosophila posterior midgut is maintained by pluripotent stem cells. Nature 439, 470–474 (2006).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Micchelli, C. A. & Perrimon, N. Evidence that stem cells reside in the adult Drosophila midgut epithelium. Nature 439, 475–479 (2006).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Ohlstein, B. & Spradling, A. Multipotent Drosophila intestinal stem cells specify daughter cell fates by differential Notch signaling. Science 315, 988–992 (2007).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Amcheslavsky, A., Jiang, J. & Ip, Y. T. Tissue damage-induced intestinal stem cell division in Drosophila. Cell Stem Cell 4, 49–61 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Salle, J. et al. Intrinsic regulation of enteroendocrine fate by Numb. EMBO J. 36, 1928–1945 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gao, P. et al. Deterministic progenitor behavior and unitary production of neurons in the neocortex. Cell 159, 775–788 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Beumer, J. & Clevers, H. Cell fate specification and differentiation in the adult mammalian intestine. Nat. Rev. Mol. Cell Biol. 22, 39–53 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Jiang, H. et al. Cytokine/Jak/Stat signaling mediates regeneration and homeostasis in the Drosophila midgut. Cell 137, 1343–1355 (2009).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Biteau, B., Hochmuth, C. E. & Jasper, H. Maintaining tissue homeostasis: dynamic control of somatic stem cell activity. Cell Stem Cell 9, 402–411 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Josserand, M. et al. Chromatin state transitions in the Drosophila intestinal lineage identify principles of cell-type specification. Dev. Cell 58, 3048–3063 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zhang, S. et al. Eclosion muscles secrete ecdysteroids to initiate asymmetric intestinal stem cell division in Drosophila. Dev. Cell 59, 125–140 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wu, S. et al. Apical–basal polarity precisely determines intestinal stem cell number by regulating Prospero threshold. Cell Rep. 42, 112093 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Guo, Z. & Ohlstein, B. Stem cell regulation. bidirectional Notch signaling regulates Drosophila intestinal stem cell multipotency. Science 350, aab0988 (2015).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chen, J. et al. Transient Scute activation via a self-stimulatory loop directs enteroendocrine cell pair specification from self-renewing intestinal stem cells. Nat. Cell Biol. 20, 152–161 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zeng, X. & Hou, S. X. Enteroendocrine cells are generated from stem cells through a distinct progenitor in the adult Drosophila posterior midgut. Development 142, 644–653 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Beehler-Evans, R. & Micchelli, C. A. Generation of enteroendocrine cell diversity in midgut stem cell lineages. Development 142, 654–664 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bardin, A. J., Perdigoto, C. N., Southall, T. D., Brand, A. H. & Schweisguth, F. Transcriptional control of stem cell maintenance in the Drosophila intestine. Development 137, 705–714 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Antonello, Z. A., Reiff, T., Ballesta-Illan, E. & Dominguez, M. Robust intestinal homeostasis relies on cellular plasticity in enteroblasts mediated by miR-8–Escargot switch. EMBO J. 34, 2025–2041 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Buchon, N. et al. Morphological and molecular characterization of adult midgut compartmentalization in Drosophila. Cell Rep. 3, 1725–1738 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Biteau, B. & Jasper, H. Slit/Robo signaling regulates cell fate decisions in the intestinal stem cell lineage of Drosophila. Cell Rep. 7, 1867–1875 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liang, J., Balachandra, S., Ngo, S. & O’Brien, L. E. Feedback regulation of steady-state epithelial turnover and organ size. Nature 548, 588–591 (2017).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • O’Brien, L. E., Soliman, S. S., Li, X. & Bilder, D. Altered modes of stem cell division drive adaptive intestinal growth. Cell 147, 603–614 (2011).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Guo, Z., Driver, I. & Ohlstein, B. Injury-induced BMP signaling negatively regulates Drosophila midgut homeostasis. J. Cell Biol. 201, 945–961 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lee, T. & Luo, L. Mosaic analysis with a repressible cell marker for studies of gene function in neuronal morphogenesis. Neuron 22, 451–461 (1999).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • de Navascues, J. et al. Drosophila midgut homeostasis involves neutral competition between symmetrically dividing intestinal stem cells. EMBO J. 31, 2473–2485 (2012).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Snippert, H. J. et al. Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 143, 134–144 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Simons, B. D. & Clevers, H. Strategies for homeostatic stem cell self-renewal in adult tissues. Cell 145, 851–862 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Reiff, T. et al. Notch and EGFR regulate apoptosis in progenitor cells to ensure gut homeostasis in Drosophila. EMBO J. 38, e101346 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lopez-Garcia, C., Klein, A. M., Simons, B. D. & Winton, D. J. Intestinal stem cell replacement follows a pattern of neutral drift. Science 330, 822–825 (2010).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Biteau, B., Hochmuth, C. E. & Jasper, H. JNK activity in somatic stem cells causes loss of tissue homeostasis in the aging Drosophila gut. Cell Stem Cell 3, 442–455 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Buchon, N., Broderick, N. A., Poidevin, M., Pradervand, S. & Lemaitre, B. Drosophila intestinal response to bacterial infection: activation of host defense and stem cell proliferation. Cell Host Microbe 5, 200–211 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Schuettengruber, B., Bourbon, H. M., Di Croce, L. & Cavalli, G. Genome regulation by Polycomb and Trithorax: 70 years and counting. Cell 171, 34–57 (2017).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Steffen, P. A. & Ringrose, L. What are memories made of? How Polycomb and Trithorax proteins mediate epigenetic memory. Nat. Rev. Mol. Cell Biol. 15, 340–356 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tauc, H. M. et al. Age-related changes in polycomb gene regulation disrupt lineage fidelity in intestinal stem cells. eLife 10, e62250 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Brand, M., Nakka, K., Zhu, J. & Dilworth, F. J. Polycomb/Trithorax antagonism: cellular memory in stem cell fate and function. Cell Stem Cell 24, 518–533 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Veneti, Z. et al. Polycomb-mediated silencing of miR-8 is required for maintenance of intestinal stemness in Drosophila melanogaster. Nat. Commun. 15, 1924 (2024).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Schmitges, F. W. et al. Histone methylation by PRC2 is inhibited by active chromatin marks. Mol. Cell 42, 330–341 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tie, F. et al. CBP-mediated acetylation of histone H3 lysine 27 antagonizes Drosophila Polycomb silencing. Development 136, 3131–3141 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • McKay, D. J. et al. Interrogating the function of metazoan histones using engineered gene clusters. Dev. Cell 32, 373–386 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang, W. et al. Probing the function of metazoan histones with a systematic library of H3 and H4 Mutants. Dev. Cell 48, 406–419 (2019).

    Article 
    PubMed 

    Google Scholar
     

  • Gunesdogan, U., Jackle, H. & Herzig, A. A genetic system to assess in vivo the functions of histones and histone modifications in higher eukaryotes. EMBO Rep. 11, 772–776 (2010).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Coleman, R. T. & Struhl, G. Causal role for inheritance of H3K27me3 in maintaining the OFF state of a Drosophila HOX gene. Science 356, eaai8236 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liefke, R. et al. Histone demethylase KDM5A is an integral part of the core Notch–RBP-J repressor complex. Genes Dev. 24, 590–601 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Schwanbeck, R. The role of epigenetic mechanisms in Notch signaling during development. J. Cell. Physiol. 230, 969–981 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Guenin, L. et al. Spatio-temporal expression of Prospero is finely tuned to allow the correct development and function of the nervous system in Drosophila melanogaster. Dev. Biol. 304, 62–74 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zeng, X., Chauhan, C. & Hou, S. X. Characterization of midgut stem cell- and enteroblast-specific Gal4 lines in Drosophila. Genesis 48, 607–611 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kaya-Okur, H. S. et al. CUT&Tag for efficient epigenomic profiling of small samples and single cells. Nat. Commun. 10, 1930 (2019).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li, Z. et al. A switch in tissue stem cell identity causes neuroendocrine tumors in Drosophila gut. Cell Rep. 30, 1724–1734 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wang, C., Guo, X., Dou, K., Chen, H. & Xi, R. Ttk69 acts as a master repressor of enteroendocrine cell specification in Drosophila intestinal stem cell lineages. Development 142, 3321–3331 (2015).

    CAS 
    PubMed 

    Google Scholar
     

  • Yin, C. & Xi, R. A phyllopod-mediated feedback loop promotes intestinal stem cell enteroendocrine commitment in Drosophila. Stem Cell Rep. 10, 43–57 (2018).

    Article 

    Google Scholar
     

  • Reinberg, D. & Vales, L. D. Chromatin domains rich in inheritance. Science 361, 33–34 (2018).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Obniski, R., Sieber, M. & Spradling, A. C. Dietary lipids modulate Notch signaling and influence adult intestinal development and metabolism in Drosophila. Dev. Cell 47, 98–111 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yu, Z. et al. Nutrient-sensing alteration leads to age-associated distortion of intestinal stem cell differentiating direction. Nat. Commun. 15, 9243 (2024).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • He, L., Si, G., Huang, J., Samuel, A. D. T. & Perrimon, N. Mechanical regulation of stem-cell differentiation by the stretch-activated Piezo channel. Nature 555, 103–106 (2018).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gao, J. et al. Dietary l-Glu sensing by enteroendocrine cells adjusts food intake via modulating gut PYY/NPF secretion. Nat. Commun. 15, 3514 (2024).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lin, H.-H. et al. A nutrient-specific gut hormone arbitrates between courtship and feeding. Nature 602, 632–638 (2022).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Vo, L. T. et al. Regulation of embryonic haematopoietic multipotency by EZH1. Nature 553, 506–510 (2018).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Meng, Y. & Nerlov, C. Epigenetic regulation of hematopoietic stem cell fate. Trends Cell Biol. 35, 217–229 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Holsopple, J. M., Cook, K. R. & Popodi, E. M. Enteroendocrine cell expression of split-GAL4 drivers bearing regulatory sequences associated with panneuronally expressed genes in Drosophila melanogaster. MicroPubl. Biol. https://doi.org/10.17912/micropub.biology.000628 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hay, B. A., Wolff, T. & Rubin, G. M. Expression of baculovirus P35 prevents cell death in Drosophila. Development 120, 2121–2129 (1994).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hay, B. A., Wassarman, D. A. & Rubin, G. M. Drosophila homologs of baculovirus inhibitor of apoptosis proteins function to block cell death. Cell 83, 1253–1262 (1995).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kidd, S., Lieber, T. & Young, M. W. Ligand-induced cleavage and regulation of nuclear entry of Notch in Drosophila melanogaster embryos. Genes Dev. 12, 3728–3740 (1998).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Harrison, D. A. & Perrimon, N. Simple and efficient generation of marked clones in Drosophila. Curr. Biol. 3, 424–433 (1993).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ohno, K., McCabe, D., Czermin, B., Imhof, A. & Pirrotta, V. ESC, ESCL and their roles in Polycomb group mechanisms. Mech. Dev. 125, 527–541 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Dura, J. M. et al. A complex genetic locus, polyhomeotic, is required for segmental specification and epidermal development in D. melanogaster. Cell 51, 829–839 (1987).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Guo, X. et al. The cellular diversity and transcription factor code of Drosophila enteroendocrine cells. Cell Rep. 29, 4172–4185 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Guo, Z., Han, Y., Jiang, Q. & Dong, T. Code for regional fitting the symmetric division ratio. Figshare https://doi.org/10.6084/m9.figshare.31311136 (2026).

  • Guo, Z., Jiang, Q., Han, Y. & Dong, T. Code for EEC proportion simulation. Figshare https://doi.org/10.6084/m9.figshare.31311127 (2026).

  • Guo, Z. CUT_Tag codes and files. Figshare https://doi.org/10.6084/m9.figshare.29569391 (2025).

  • Guo, Z., Yuan, Q. & Dong, T. R code for data visualization. Figshare https://doi.org/10.6084/m9.figshare.32617422 (2026).

  • RELATED ARTICLES

    Most Popular

    Recent Comments