Lymphology has made remarkable progress in last two decades. Various techniques to identify lymphatic vessels in the body have been developed and brought about great changes in this fields including both basic and clinical research. Although multiple achievements have been made by our predecessors over time, however, many fundamental questions in this field of lymphology still remain unresolved. We recently described these issues in our review articles, titled "Seven Mysteries of the Lymphatics" and "Some Remaining Mysteries in Lymphology: Relationships between Lymph and Fat". In this review, we described several particularly important topics and interesting points being considered from various perspectives by emphasizing the unresolved mysteries.

Studies on the lymphatic system have made remarkable progress with the discovery of lymphatic endothelial cell-specific markers. To discover lymphatic endothelial cell-specific markers, we adopted a Freund's incomplete adjuvant (FIA) -induced lymphangioma model in rodents. The tumor was used as an antigen source of mouse lymphatic endothelium to produce monoclonal antibodies. We obtained LA102, which recognizes lymphatic endothelial cells, but not blood vessel endothelial cells. We found LA102 to be a homolog of mouse CD90.2 (Thy-1.2). Using LA102 and other specific markers for microvessels, including lectins, we have developed 3D-imaging techniques to characterize lymphatic networks to differentiate from blood vessels. This model has also been adopted to investigate the relationship between peritoneal mesothelium and lymphatic endothelium. At three days after FIA injection, simple squamous mesothelial cells became cuboidal and detached from each other to lose their polarity and formed multi layers. Various-sized fat droplets gradually fused with each other, and the fat-storing cells became large fat cells or formed large chimeric follicular structures. At four weeks or later, these cell masses formed tubular structures draining the fat out of the peritoneal cavity. Taking up fat (FIA) droplets, not only podoplanin⁺ mesothelial cells, but also bone marrow-derived macrophages and some interstitial mesenchymal cells were involved in tumorigenicity. We suggest a sequential change from mesothelial to lymphatic endothelial cells via fat-storing lymphangioma cells after FIA stimulation. These phenomena seem to be a defense mechanism, where mesothelial-endothelial transformation might occur via fat incorporation to drain the extrinsic adjuvant oil out of the peritoneal cavity. The significance of FIA-induced lymphangiomas and mesothelial cell diversity might be important for the interrelationship between fat cells and lymphatic endothelial cells.

Abnormal cell proliferation, a characteristic of malignant tumors, is accompanied by angiogenesis, through a complex molecular pathway involving various vascular growth factor groups. The abnormal blood vessels formed by the cancer establish a hypoxic and low pH environment in the vicinity of the tumor, causing a decrease in immunogenicity. Since the cancer cells produce immunosuppressive factors that further induce the related cells, an immunosuppressive environment optimal for the growth of the tumor is established. Although the gastrointestinal tract maintains homeostasis by specific immune surveillance mechanisms involving the lymph nodes and Peyer's patch, once a malignant tumor develops, a system that escapes the monitoring mechanism by taking advantage of the immune-checkpoint route is newly generated. Although normalization of the tumor microenvironment using molecular target drugs has attracted attention in recent years as the next generation cancer treatment, it is reported that this method also affects the host immune mechanism simultaneously. However, since many aspects of this intervention including the detailed mechanism of the immune mechanism for tumor microenvironment normalization, the prognosis, and the side-effects are still unclear, the clinical applications are not feasible yet. We believe that "normalization of the tumor environment and tackling its mechanism," can construct a host environment that maximizes the therapeutic effect of anti-cancer therapies including chemotherapy, immunotherapy, and radiation therapy, in addition to restoring the host immunity of the gastrointestinal tract. In other words, this could become the next generation cancer treatment. This review article focuses on tumor angiogenesis, tumor microenvironment, and the specific immune surveillance mechanism of the gastrointestinal tract, and finally proposes what is necessary for the "reprogramming of tumor microenvironment".

During various events in the reproductive period (viz., menstruation and delivery) of a woman, the endometrium displays phenomenal regenerative ability to repeat the cycle of shedding and regeneration. However, the mechanisms responsible for complete inner membrane repair and regeneration remain mostly unexplored. Gynecological diseases, such as placenta accreta and implantation failure, are caused by insufficient repair of the endometrium. However, because the mechanism behind these diseases are unclear, there are no known preventive methods. Changes in oxygen concentration in the endometrium are known to be involved in defense against bacteria and trophoblast invasion for the establishment of pregnancy. Additionally, it is also thought to affect angiogenesis and tissue repair. The difficulty of obtaining human samples, hampers investigation along this line of research. Using a postpartum mouse model and mice with sub-involuted uterus, we have reported that changes in intrauterine oxygen concentration, including hypoxia, due to involution of the uterine smooth muscle are responsible for scarless endometrial repair. Elucidation of the regenerating mechanism of the endometrium provides possibilities to prevent complications in obstetrics and gynecology, and a strong basis for scarless tissue repair through a new approach of generating microenvironments based on oxygen concentration adjustment in normal tissues. In this review, we discuss the role of microenvironment in the process of healing and regeneration of the endometrium.

Metabolic syndrome (MetS) is a complex disorder combining hypertension, obesity, dyslipidemia, and insulin resistance accompanying abnormal adipose deposition and function. MetS is associated with the development of atherosclerotic cardiovascular disease, and contributes to the development of chronic kidney disease (CKD). A close relationship between MetS and increased risk of developing renal damage has been established. Early diagnosis and treatment of MetS is essential in the forming of strategies to prevent CKD as a result of MetS. Several findings have indicated that the activation of the intrarenal renin-angiotensin system (RAS) may play an important role in the progression of MetS to CKD. Therefore, RAS blockade is a first-line therapeutic target for preventing progression of MetS to CKD. The aim of this article is to provide an overview of the concept of MetS, and to discuss the management of CKD in patients with MetS.