Stem cell-driven lymphatic remodeling coordinates tissue regeneration

Shiri Gur-Cohen ¹ Hanseul Yang Sanjeethan C Baksh ¹ Yuxuan Miao John Levorse Raghu P. Kataru ² Xiaolei Liu June Dela Cruz-Racelis ¹ Babak J. Mehrara Elaine Fuchs

¹Howard Hughes Medical Institute, The Rockefeller University, USA
²Department of Surgery, Plastic and Reconstructive Surgery Service, Memorial Sloan Kettering Cancer Center, USA
³Center of Vascular and Developmental Biology, Feinberg Cardiovascular and Renal Research Institute, Northwestern University, USA

Tissues rely on stem cells (SCs) for homeostasis and wound-repair. SCs reside in specialized microenvironments (niches) whose complexities and roles in orchestrating tissue growth are still unfolding. SC:niche interactions must be tightly regulated to avoid either excessive SC activity, which can cause tissue overgrowth and SC exhaustion, or insufficient activity, which can contribute to aging and defective tissue regeneration. Here, using 3-dimensional deep imaging and molecular genetic approaches, we identify lymphatic capillaries as critical SC-niche components. In skin, lymphatics form intimate networks around hair follicle (HF) SCs. When HFs regenerate, lymphatic:SC connections become dynamic. Seeking understanding, we unravel a secretome switch within SCs that controls lymphatic behavior. Resting SCs express Angiopoietin-like 7 (Angptl7), promoting lymphatic drainage. Activated SCs switch to Angptl4, sparking transient lymphatic dissociation and reduced drainage. When lymphatics are perturbed or the secretome switch is disrupted, HFs cycle precociously and tissue regeneration becomes asynchronous. In unearthing lymphatic capillaries as a critical new SC-niche element, we’ve learned how SCs coordinate their activity across a tissue.