Lymphatic vessels interact dynamically with the hair follicle stem cell niche during skin regeneration in vivo

Abstract

Lymphatic vessels are essential for skin fluid homeostasis and immune cell trafficking. Whether the lymphatic vasculature is associated with hair follicle regeneration is, however, unknown. Here, using steady and live imaging approaches in mouse skin, we show that lymphatic vessels distribute to the anterior permanent region of individual hair follicles, starting from development through all cycle stages and interconnecting neighboring follicles at the bulge level, in a stem cell‐dependent manner. Lymphatic vessels further connect hair follicles in triads and dynamically flow across the skin. At the onset of the physiological stem cell activation, or upon pharmacological or genetic induction of hair follicle growth, lymphatic vessels transiently expand their caliber suggesting an increased tissue drainage capacity. Interestingly, the physiological caliber increase is associated with a distinct gene expression correlated with lymphatic vessel reorganization. Using mouse genetics, we show that lymphatic vessel depletion blocks hair follicle growth. Our findings point toward the lymphatic vasculature being important for hair follicle development, cycling, and organization, and define lymphatic vessels as stem cell niche components, coordinating connections at tissue‐level, thus provide insight into their functional contribution to skin regeneration.

Relationship between shape of peripheral initial lymphatics and efficiency of mechanical stimulation–induced lymph formation

“…The initial lymphatics of the mouse skin are usually observed between or near the hair follicles (Figures 2B and 8). These observations are compatible with those of an earlier study that showed an interaction between the initial lymphatics and the hair follicle stem cell niche 24. Our present observations suggest that hairs have promoting effects on lymph formation by stretching the initial lymphatics.…”

“…These observations are compatible with those of an earlier study that showed an interaction between the initial lymphatics and the hair follicle stem cell niche. 24 Our present observations suggest that hairs have promoting effects on lymph formation by stretching the initial lymphatics. On the other hand, lymphocytes such as T-cells, B-cells, macrophages, Langerhans' cells, and dendritic cells are known to be taken up into the initial lymphatics.…”

Functional complexity of hair follicle stem cell niche and therapeutic targeting of niche dysfunction for hair regeneration

“…Due to the continuous advance in hair research, more and more cell types (Fig. 2), including DP cells, adipose tissue, lymphatic vessels, nerves and immune cells, are identified to be contributing to the HFSC niche [15,16,[25][26][27][28][29][30][31][32][33][34][35][36], unveiling the complexity and sophistication in the interaction of HFSCs with its environment. Since activating and inhibitory signals can both be present in the HFSC niche, the probability of HFSC activation is the readout of the summation of both activating and inhibitory signals [37,38].…”

The aging skin microenvironment dictates stem cell behavior

“…Prolonged cross-talk between the DP and adjacent HFSCs is needed to enter the hair growth phase. Additional inputs from the lymphatic capillaries, adipose tissue, dermal fibroblasts, immune cells (e.g., macrophages and regulatory T cells), and HFSC progeny themselves have all been reported to impact HFSC behavior, and participate in the transition from resting state to active HF regeneration and hair growth (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). The lymphatic network also integrates the activity of HFSCs across the tissue (28).…”