Dermal tissue mechanics and lymphatic function in homeostasis and inflammation
Dermal lymphatic capillaries (LCs) play a key role in maintaining the fluid balance of the skin by draining fluid from the interstitium and transporting it back into the blood circulation. Under homeostatic conditions, the drainage rate of LCs surpasses that of blood filtration, leaving the dermal interstitium in an under-hydrated gel-like state. However, during inflammation, this delicate balance is disrupted, leading to the formation of edema and consequent swelling of the tissue.
LCs drain fluid via two routes. A trans-cellular route involves trans-endothelial transport of vesicles, and a para-cellular route, which entails fluid entering the lumen of LCs via gaps in between the lymphatic endothelium. Evidence suggests that the specialized endothelium of LCs acts as one-way valves and that the function of these valves might be mechano-sensitive, reacting to physical stimuli such as fluid pressure and mechanical loadings.
Drainage of dermal LCs still remains enigmatic due to a lack of understanding of the nature and impact of dermal tissue forces in homeostatic and inflammation states on LC function. Further complexities arise from the need to study LC function in living organisms.
We employ intravital microscopy to study dermal LCs and dermal interstitium in murine ear skin in homeostatic and inflammation states. Using laser-ablation experiments, we investigate and manipulate the tension of fibroblasts, elastin, and collagen and measure their effects on single LCs. Furthermore, FRAP experiments of injected tracers are utilized to investigate fluid exchange across the LC endothelium at the single LC level.
Furthermore, we are developing a novel multi-layer skin model based on first principles to simulate fluid flow in and around LCs. This approach will help us better understand experimental data and go beyond what is experimentaly feasible.
The combined approach of experiments and fluid simulations aims to elucidate how dermal tissue forces affect LC-mediated drainage of interstitial fluids, particularly in states of homeostasis and inflammation. We aim to generate new fundamental insights in the functioning of lymphatics which could have potential implications related to tissue physiology, immunology and cancer.
People involved in this project: Frank Assen