UC San Diego

Adult stem cells (SCs) are defined by their ability to self-renew to maintain a SC pool while preserving their potential to differentiate, ensuring tissue homeostasis. Yet, how SC fate decisions are dictated and synchronized across a tissue remains poorly understood. SCs are surrounded by and communicate with their supporting microenvironments, or “niches,” for tissue regeneration. Recent evidence has revealed the lymphatic vascular system as a new niche entity for adult SCs across epithelial tissues, including hair follicle stem cells (HFSCs) in the skin. However, whether lymphatic vasculature can instruct SC fate decisions in tissue renewal is unknown. Here, we investigate how HFSC fate decisions and differentiation potential are guided by their spatial proximity to lymphatic niches during homeostatic tissue regeneration. Using deep 3-dimensional imaging of the regenerated hair follicles (HFs), coupled with genetic lineage tracing and conditional lymphatic ablation models, we identify an asymmetric lymphatic architecture surrounding the HFSCs across the horizontal axis of the follicle. Through tracking SC proliferation rates and detailed temporal lineage tracing, our findings reveal a clonal imbalance in the regenerated HF. We demonstrate the most regenerating SCs exhibit earlier cell divisions and originate near lymphatic capillaries. In contrast, SCs from later division waves, which reside farther from the lymphatics, primarily maintain self-renewal rather than contribute to differentiation and tissue regeneration. This study provides a further direction to understand the lymphatic-stem cell duet in tissue regeneration, which could have important clinical implications for stem cell transplantation and therapeutic intervention to advance wound response in degenerative pathologies.