Retrotransposon Control and Function in Adult Stem Cells: From Local Homeostasis to Systemic Diseases

Retrotransposons (RTEs), which comprise nearly half of the mammalian genome, are silenced in adult somatic tissues but can be reactivated by physiological stimuli and in diseases. Here, we focus on adult regenerative tissues, particularly blood and skin, where RTE regulation requires a delicate balance between maintaining faithful silencing and harnessing physiological RTE activity to support stem cell maturation, stress responses, and interactions with tissue niches, and excessive reactivation can lead to stem cell exhaustion and tissue dysfunction. We summarize studies of RE-derived nucleic acids that, when aberrantly activated, engage innate immune sensors and trigger antiviral responses, linking RTE activity to inflammatory disorders. We further review experimental evidence in cancer, where RTE reactivation creates a battleground between antiviral defense and immune evasion, and emerging evidence suggesting that RTEs may mediate communication between peripheral tissues and the hematopoietic system. Finally, while experimental evidence is promising, clinical studies targeting RTE activity have produced mixed outcomes. We therefore conclude by highlighting the need for deeper mechanistic investigations.