DNA Damage Leads to Inflammation in the Stem Cell Microenvironment

This open access paper reviews the relationship between DNA damage and inflammation in the specialized environments that support stem cell populations. Aging produces many changes that lead to reduced stem cell function. Changes in the niche, the supporting cells that help to ensure stem cells retain their function, are of increasing interest to the research community. The chronic inflammation of aging is also an area of growing study. The inflammatory response to rising levels of DNA damage with age in stem cells and stem cell niches is an interesting overlap between these two parts of the field.

DNA damage profoundly affects the inflammatory microenvironment where stem cells reside, which can have detrimental consequences for their maintenance and long-term function. Indeed, it has been shown that DNA damage-induced immunostimulatory events can lead to tissue-specific stem cell exhaustion leading to degenerative conditions. Conversely, the release of specific cytokines can also positively impact tissue-specific stem cell plasticity and regeneration of damaged tissues in addition to enhance cancer stem cell activity leading to tumor progression.

This review provides an overview of the main biological mechanisms linked to changes in the stem cell microenvironment and activation of immune processes upon DNA damage induction. Although recent findings have brought to light new insights into these DNA damage-related inflammatory events, some questions remain unanswered. For instance, it is still not clear how to exploit the production of inflammatory cytokines in order to promote on one side immunostimulatory responses against the tumor and on the other side immunosuppressive responses against aging-related degenerative conditions. Especially since the activation of DNA and RNA sensors might change depending on the specific stimulus and cell type.

DNA damage-induced senescence plays a pivotal role in cell cycle arrest and can be used as a barrier against tumor expansion; however, due to the accompanying senescence-associated secretory phenotype (SASP), it is also responsible for loss of tissue function, aging-related diseases and tumor progression. Therefore, further studies are required to understand how to properly modulate the exposure to SASP factors toward the promotion of a regenerative state and against detrimental effects, such as paracrine senescence of neighboring cells and chronic inflammation. Furthermore, it would be interesting to explore how different types of DNA damage can influence senescence and its SASP phenotype in different adult stem cells.

Further understanding of DNA damage immunomodulatory mechanisms, cell- and stimulus-specific variability might unravel novel strategies to regulate the stem cell microenvironment. As mentioned in this review, genotoxic stress can affect the stem cell microenvironment leading to stem cell exhaustion, likely through a combination of a decline in cell number and functional capacity, with the emergence of aging-related pathologies. On the other hand, due to their self-renewal properties, cancer stem cells are also affected by DNA damage and the associated inflammatory microenvironment, which can worsen tumor control and treatment efficacy. Understanding the mechanistic links between stem cell properties and microenvironmental changes initiated upon DNA damage will be critical to counteract the functional decline of adult stem cells in aging-related diseases and effectively diminish cancer stem cell activity and expansion.

Link: https://doi.org/10.3389/fcell.2021.729136

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