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Three-Dimensional Visualization of Lymphatic Vessels in Human Skin and Their Structural Changes During Lymphedema

The lymphatic vessels of the skin, comprising capillaries and collecting vessels, have key roles in waste removal and immune responses, and are essential ...

MIRAI Technology Institute, Shiseido Co., Ltd.

Aging is associated with a progressive decline in muscle mass, strength, and quality. We have previously demonstrated the important role of the blood vasculature system in ultraviolet (UV) light-induced changes in skin and its molecular mechanisms. Whereas recent findings revealed structural alterations of the cutaneous vasculature in aged and photoaged human skin, structural changes of blood vessels in skeletal muscles with age have remained unclear. Although, facial skeletal muscles could be involved in skin-aging, here, we show-for the first time-that, in the lateral great muscle, the cross-sectional muscle fiber area and vessels size were decreased in older skin compared with that in younger skin. In the orbicularis oculi muscle, no significant interaction between age and the muscle fiber area was observed. However, a significantly decreased ratio of muscle area was indicated in older skin compared with that in younger skin. Interestingly, the pericyte-covered vessels ratio was decreased in older skin. Therefore, we found that the skeletal muscle capillary destabilizes with age. In summary, we revealed that the lateral great muscle and the orbicularis oculi muscle fibers become thinner with age due to the destabilization of skeletal muscle capillaries. Therapeutic targeting of muscle capillaries might affect the decline of skeletal muscles with age and could potentially regulate muscle/skin-aging.

Age-related structural alterations of skeletal muscles and associated capillaries.

Microvascular dysfunction accompanied by a dramatic alteration of stable capillary structure is a major hallmark of numerous age-related diseases. In skin, although the role of angiogenesis during dermal reconstitution is well documented, the functional relevance of the extracellular matrix (ECM) stiffness to vascular remodeling and its molecular mechanisms was poorly understood. Here, we developed an ex vivo 3-dimensional angiogenic model using human fat, revealing that "appropriate" stiffness induces vascular maturation associated with upregulated APJ expression, whereas the overexpression of APJ promotes the formation of large vessels even in the absence of the "appropriate" stiffness. Taken together, APJ could be a novel mechanotransducer that accelerates the maturation of cutaneous blood vessels, leading to the prevention of human skin aging.

Blood vessels sense dermal stiffness via a novel mechanotransducer, APJ.

Apelin provides an alternative function to estrogen in regulating lymphatic vascular integrity.

Secondary lymphedema often develops after lymph node dissection or radiation therapy for cancer treatment, resulting in marked skin fibrosis and increased stiffness owing to insufficiency of the lymphatic system caused by abnormal structure and compromised function. However, little is known about the associated changes of the dermal lymphatic vessels. In this study, using the lower limb skin samples of patients with secondary lymphedema, classified as types 1-4 by lymphoscintigraphy, we first confirmed the presence of epidermal thickening and collagen accumulation in the dermis, closely associated with the progression of lymphedema. Three-dimensional characterization of lymphatic capillaries in skin revealed prominent lymphangiogenesis in types 1 and 2 lymphedema. In contrast, increased recruitment of smooth muscle cells accompanied by development of the basement membrane in lymphatic capillaries was observed in types 3 and 4 lymphedema. Remarkably, the junctions of dermal lymphatic capillaries were dramatically remodeled from a discontinuous button-like structure to a continuous zipper-like structure. This finding is consistent with previous findings in an infection-induced mouse model. Such junction tightening (zippering) could reduce fluid transport and cutaneous viral sequestration during the progression of lymphedema and might explain the aggravation of secondary lymphedema. These findings may be helpful in developing stage-dependent treatment of patients with lymphedema.

Lymphangiogenesis and Lymphatic Zippering in Skin Associated with the Progression of Lymphedema.

Building affiliative relationships with others is important for mental health. Recently, robots have been expected to play a role in improving mental health, but there is little scientific evidence as to whether they can build affiliative relationships with humans. To investigate that, we conducted studies combining behavior, physiology and questionnaires for companion robot Owners and Non-Owners. The results reveal that the steady-state concentration of oxytocin, a hormone related to affiliative relationships, was significantly higher in Owners than in Non-Owners. In addition, the Owners showed more behaviors indicative of intimacy than the Non-Owners. These results suggest that humans can build affiliative relationships with robots. Fifteen minutes of contact with the robot decreased the concentration of cortisol in both groups, suggesting that even a brief contact can contribute to improving mental health. Therefore, relationships between humans and robots may be one option to improve mental health and enhance well-being.

Article	Year
Age-related structural alterations of skeletal muscles and associated capillaries. Angiogenesis\| PubMed ID: 31993832	2020
Blood vessels sense dermal stiffness via a novel mechanotransducer, APJ. Angiogenesis\| PubMed ID: 34617195	2022
Apelin provides an alternative function to estrogen in regulating lymphatic vascular integrity. Journal of dermatological science\| PubMed ID: 37580204	2023
Lymphangiogenesis and Lymphatic Zippering in Skin Associated with the Progression of Lymphedema. The Journal of investigative dermatology\| PubMed ID: 37660779	2024
Higher oxytocin concentrations occur in subjects who build affiliative relationships with companion robots. iScience\| PubMed ID: 38162035	2023

Kentaro Kajiya

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