Abstract
Stem cells maintain tissue architecture by replacing differentiated cells at steady state and upon injury. Implementing this cornerstone role requires protection of stem cells from pathogens and from the toxic effects of immune system activation. However, the pro-inflammatory innate immune mechanisms that protect differentiated cells from infection are poorly functional in stem cells. Instead, stem cells employ other specific defence mechanisms, such as antiviral RNA interference. At steady state, the proliferation and differentiation of tissue stem cells is regulated by multiple cell types, including immune cells. Following sterile tissue injury or during infection, the immune response — in addition to controlling pathogens and clearing cell debris — orchestrates tissue repair by fine-tuning stem cell activity, through direct cell–cell contacts and via inflammatory mediators such as cytokines. There is thus stem–immune cross-talk that is fundamental to the maintenance of tissue homeostasis. Inflammageing, which is defined as the age-driven elevation of inflammation and is associated with an altered immune cell composition, profoundly affects this stem–immune cross-talk, impacting the ability to repair tissues and participating in ageing of the whole organism.
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Acknowledgements
The author apologizes to colleagues whose work was omitted due to space constraints. The author thanks members of his team, scientists of the Immunity and Cancer Unit of Institut Curie and the Reis e Sousa laboratory of the Crick Institute for fruitful discussions and critical reading of the manuscript. This work is supported by a European Research Council (ERC) Starting Grant (STEMGUARD 101075865), by the grant ‘Impact Santé’ supported by Agence Nationale de la Recherche (ANR) under France 2030 (ANR-24-RRII-0005) on funds administered by Inserm, by funding from the programme France 2030 launched by the French Government (ANR 11 LBX 0043, part of IDEX PSL ANR-10-IDEX-0001-02), by the Major Research Program of PSL Research University ‘DEVINE’ launched by PSL Research University and implemented by ANR (ANR-10-IDEX-0001), by a Jeune Équipe grant from the Fondation pour la Recherche Médicale (ConvAJE202110014409) and by funding from Institut Curie.
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Glossary
- Adult stem cells
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Cells, located in specific niches within adult tissues, that are undifferentiated cells that generate tissue-specific differentiated cells upon division. Contrary to embryonic stem cells (ES cells), adult stem cells can give rise to a limited number of differentiated cell types. Depending on the tissue, adult stem cells are constantly cycling (intestinal stem cells (IS cells)), alternating between periods of cycling and quiescence (hair follicle stem cells (HFS cells) of the skin) or quiescent without the activation of tissue repair (muscle stem cells (MuS cells)).
- Embryonic stem cells
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(ES cells). Pluripotent cells isolated from the inner cell mass of blastocysts (early-stage embryos), which can be differentiated in cells of the three primary germ layers. These cells have been widely used as a stem cell model, including in infection studies, due to their relative simplicity of isolation and culture. One disadvantage of using ES cells for pathogen infection relates to a poor physiological relevance, as such cells are rarely in contact with pathogens in natural settings. Nevertheless, ES cells have been an invaluable tool for the stem cell immunity research field, and enabled the discovery of biological mechanisms whose existence was later confirmed in adult stem cells.
- Inflammageing
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This umbrella term refers to increased inflammation gradually occurring with advanced age, in the absence of infection. There are increased levels of pro-inflammatory cytokines (interferons, interleukins) in the blood and tissues of aged individuals, as well as changes in the composition of immune cells, with a bias towards the myeloid lineage to the detriment of the lymphoid lineage.
- Stem–immune cross-talk
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The interactions between stem cells and immune cells that modulate their respective activity. Stem–immune cross-talk can be mediated by direct cell–cell contact, or via the secretion of soluble mediators such as cytokines. If research has largely focused on immune cells regulating stem cells, more recent data document that stem cells can also influence immune cells.
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Poirier, E.Z. How stem cells respond to infection, inflammation and ageing. Nat Rev Immunol (2025). https://doi.org/10.1038/s41577-025-01203-z
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DOI: https://doi.org/10.1038/s41577-025-01203-z
