Toshitaka Oohashi
Succeeded in 2000 in cloning HAPLN2, or hyaluronan and proteoglycan link protein 2, and started research into HA and proteoglycan. Both the perineuronal nets and cartilage extracellular matrix form aggregation of HA and proteoglycan. They seem to act differently, but have similar aggregates.
Professor, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University since 2014. Enjoys participating in academic meetings in Europe.
The 12th International Conference on Hyaluronan (HA 2019) was held at the Hilton Hotel near Cardiff Castle located in the center of Cardiff, the capital of Wales, UK, spanning five days starting from June 9, 2019. The conference was planned and organized principally by Dr. Soma Meran, Dr. Aled Phillips, Dr. Tim Bowen and Dr. Robert Steadman from Cardiff University and supported by the committee members: including Dr. Carol de la Motte (Cleveland Clinic, USA), the organizer of the last conference; Dr. Davide Vigetti (University of Insubria, Italy), the organizer of the previous conference; Dr. Anthony Day (Manchester University, UK); and Dr. Mary Cowman (NYU, USA). The international conference of International Society for Hyaluronan Sciences (ISHAS) is organized and held every two to three years. This year, the conference was held in the UK, which is split over Brexit, the withdrawal from the EU, but the conference proceeded without incident. 170 hyaluronan researchers across the world assembled to have lively discussions on latest research results.
The conference was divided into ten sessions with a total of 60 oral presentations and 123 poster presentations (including 63 flash talks), covering a wide range of themes from basic research to application of hyaluronan. The session themes were as follows:
The author (Toshitaka Oohashi) has been a researcher of hyaluronan (HA) and HA proteoglycan link protein (HAPLN) for many years and has participated several times in the International Conferences on Hyaluronan: HA2003 (Cleveland), HA2010 (Kyoto), HA2015 (Florence) and this year’s conference (the fourth time).
The first day, Professor Thomas Wight (Benaroya Research Institute, Seattle) was given a Rooster Award (an award to a researcher who makes great contribution to the application of HA to treatment) and a commemorative gift from ISHAS for his international contribution to research into HA. The Professor gave an honoree presentation. He no doubt talked animatedly about the importance of HA and Versican (“friends” of HA as stated in the abstract) in the pathogenesis of atherosclerosis. Unfortunately, the author missed his presentation because the flight from Japan arrived substantially behind schedule. The Professor raised a number of sharp questions into fundamental issues during the conference, which gave a clear indication of how he remains passionate about HA research.
The second day started with the keynote lecture by Dr. Anthony Day. HA consists of an extremely simple repeating disaccharides composed of GluNAc and GlcA and includes super high molecular mega-dalton mass range. Although it is produced exceptionally by some bacteria, HA formation is the hallmark of vertebrates and takes place in diverse tissue. The mechanism of action varies depending on the binding protein, crosslinking, degradation size and receptor. He overviewed the characteristics of HA, while analyzing the structure of HA binding proteins (HABPs) and probing into HA mechanism of action, e.g. how different HA size is detected. The details of the nine impressive sessions starting with Session 1 are given in the website below. https://ishas.org/previous-conferences/2019-ha-conference Here, the author wishes to choose and introduce several topics from personal notes.
In Session 1, Paul Noble Laboratory (Ceders-Sinai Medical Center) presented the results of single cell transcriptome analysis of embryonic lung, highlighting cell-type-specific gene expression profiling according to HA synthesis, degradation and receptor.
Professor Naoki Itano, who served as co-chair with Professor Day, gave a presentation in Session 2. Based on the fact that aggressive breast cancer cells with high HA expression produce a large quantity of huge HA and elevate HAS expression, Professor Itano has been recently focusing on the intracellular hexosamine biosynthetic pathway (HBP) associated with the biosynthesis. For the maintenance of chemotherapy-resistant cancer stem phenotype, HAS is indispensable, and hyper-O-GlcNAcylation of various proteins assists it. Professor Itano conducted and presented a joint research with Dr. Kakizaki of Hirosaki University into HAS inhibitor 4-MU in Cleveland in 2003. Their method of regulating HA biosynthesis prominently featured in this conference. The author spoke about the global deletion of the aggrecan (Acan) gene by Rosa26-CreERT2 in the flash talk. It is an effective model for analyzing the functions of the aggrecan gene after birth. The author also took this opportunity to announce Proteoglycans 2019 (organized by Professor Hideto Watanabe, Aichi Medical University) to be held in Kanazawa at the end of September.
The theme of Session 3 was HA biophysics. Doctor Ralf Richter (University of Leeds), one of the domain’s rising researchers, explained different impacts of mechanical forces on HA receptor CD44 in high shear stress in the blood vascular endothelial cells and LYVE-1 in low shear stress in the lymphatic endothelium. He also explained an assay method, in which the HA-rich/low-density vascular endothelial glycocalyx was arranged on a glass coverslip with different HA molecular weights/density and then CD44+ beads were subject to fluidic environments to verify cell-matrix interaction by reflection interference contrast microscopy (RICM).The author found that such quantitative investigation was a useful platform for HA-receptor interactions. Poster presentations and flash talks were held after lunch every day, in which young researchers talked passionately and fielded many questions.
Session 4 dealt with HA in Cancer Biology. Professor David Jackson, renowned for research into LYVE-1, attracted interest with his presentation on the exit of cells from tissues via lymphatic vessels. He demonstrated that migration of dendritic cells through lymphatic vessels required engagement between HA (about 100 nm-thick) around the dendritic cells and LYVE-1 dimers on lymphatic endothelial cells and that a transmigratory cup was formed as the dendritic cells migrated via lymph. In addition, Professor Jackson described how the engagement of cells by LYVE-1 was coordinated with the actions of key adhesion molecules including ICAM-1 and activated by local secretion of CCL21.
In Session 5 on HA Metabolism and Assembly, Alberto Passi’s Department presented the natural antisense transcript for HA synthase 2 (HAS2-AS1), which is a long-non coding RNA (lncRNA) transcribed in the opposite strand of HAS2 gene. Following previous research reports into its involvement in chromatin remodeling around HAS2 gene, Dr. Vigetti described interaction of the lncRNA with microRNA. Silencing HAS2-AS1 modified expression of 37 genes. HAS2-AS1 bound to certain microRNA and worked as a “sponge.” Professor van den Berg (Leiden University) used endothelial cell-specific tamoxifen-induced HAS2 KO mice to demonstrate glycocalyx reduction by 80% in glomerular endothelial cells; the integrity of endothelial cells was critical for glomerular structure and functions. Over time, this process developed into recapitulation of the phenotype of progressive diabetic nephropathy. The professor observed loss of glomerular endothelial HA in the renal calyx in human diabetic nephropathy. Although not recognized up to present, HA may attract attention a key component in glomerular structure and functions in diabetic nephropathy. In the flash talk, two researchers of orthopedic surgery from Nagoya University gave a presentation on HA metabolism in the cartilage. While presentations on HA metabolism in the cartilage are popular in Japan, there were only a few presentations in this conference.
In Session 6 on HA signaling, Dr Cheryl Knudson (East Carolina University) presented on CD44 endocytosis. She has accepted many Japanese students.
Session 7 dealt with Novel HA Interactions. Dr. Yu Yamaguchi is famous for research in proteoglycan and in HA as well; he cloned HAS at about the same time as Professor Itano. He identified the physiological functions of HA degrading enzyme TMEM2 and disclosed unpublished data. He continued focusing on HA degradation, the same topic as in the last conference. Extremely rapid HA metabolism (catabolism) on skin is already known; however, it has not been explained completely by HYAL, which seems to contribute most to degradation. He shed light on TMEM2 to fill the gap left by HYAL. When endogenous TMEM2 physiological activity was deleted conventionally, three germ layers of an embryo in 10.5 day did not develop normally, and no basement membrane was formed. Conventional gene knockout resulted in embryonic lethality, preventing him from studying genes in adults. Then, he also observed inducible gene knockout in adult mice. TMEM2 may be expressed on various tissue; expression of the type II transmembrane topology in the lymph nodes seems to be associated with systemic HA metabolism. At the banquet, Dr. Yamaguchi came to the table of the author’s group, giving us the precious opportunity to exchange ideas on HA metabolism in the brain and the perineuronal network functions, which the group is studying. The talk of Dr. Kwok (University of Leeds) was also interesting. She is a researcher of perineural net (PNN) like the author and previously reported that removal of chondroitin sulphate proteoglycans (CSPGs) with ChaseABC injection reactivated neuroplasticity after spinal cord injury. This time, she examined a new HA synthesis inhibitor candidate using 4-MU as lead compound and showed its effects. The inhibitor removed not only HA but also proteoglycan, including aggrecan, and restored the motor function of hind limbs.
In Session 8 on HA in Immunity and Inflammation, Dr. de la Motte (Cleveland Clinic) spoke on HA35; Dr. Nagy (Stanford University) spoke on 4-MGU, or active metabolite of 4-MU.
From eight in the morning up until after six in the afternoon, only with a lunch break, oral and poster presentations were given, followed by active discussion every day. Finishing the afternoon poster presentations on the fourth day, the participants finally took a break to go on an excursion with dinner in Caldicot Castle in the suburbs. After a 1-hour bus journey to the east, they were welcomed by soldiers clad in armor and women wearing period costume. It was drizzling. They had a very good time, sharing dinner and discussing with each other various topics under a big tent till late at night.
In the morning of the last day, the conference finished with Sessions 9 and 10 on HA in Chronic Diseases and Aging.
The author had to move to London and left the conference venue a little earlier after saying good-bye to coresearchers and friends, hopeful that participation in this conference would give renewed impetus to research.
The next conference will be held in Portland, Oregon, USA, in two years’ time in 2021.
（You can enjoy the photo gallery on HA2019 website.）
