Naoki Itano
Faculty of Life Sciences, Kyoto Sangyo University
The 11th International Conference on Hyaluronic Acid (HA 2017) was held at the Inter-Continental Hotel and Conference Center in Cleveland, Ohio, USA, for five days from June 11, 2017. Drs. Carol de la Motte and Vincent Hascall (Cleveland Clinic, USA) assumed the leading role of organizers of this conference. Alberto Passi and Davide Vigetti (University of Insubria, Italy)—the organizers of the previous conference—and Larry Sherman (Oregon Health & Science University, USA) took part in the planning and administration as organizing members. This international conference has been held under the sponsorship of the International Society for Hyaluronic Acid Sciences (ISHAS) in an interval of two to three years.
There had been concern that the number of participants from Europe might decrease as this year's conference amid the raging terrorism globally. In spite of this concern, however, more than 300 researchers from all over the world gathered and had lively discussions over the reports on latest research findings様ike in the previous conference held in Florence, Italy.
During the conference period, a total of 60 oral reports were made in 10 sessions, along with 166 poster demonstrations, presenting comprehensive programs encompassing wide-ranging contents from basic studies to application regarding hyaluronan.
With regard to the detailed contents of the research presented at each session, the readers are advised to refer to the summaries given below.
Numbers of important reports were contributed to the conference. Notably, in the basic research area, new discoveries were reported regarding the identification of new hyaluronidase. Further, complex control mechanism of hyaluronan biosynthesis was clarified, and progress was observed in the elucidation of the dynamic roles of hyaluronan in the embryonic development.
In what follows, I would like to briefly introduce the contents of the report mainly on aforementioned research.
After the opening session on the first day of the conference, a legacy session was held to commemorate Dr. Endre Alexander Balazs who passed away in 2015. Dr. Balazs, the founder of ISHAS, led the world's studies on hyaluronan as the first president of the organization. His initiative to propose application of hyaluronan as therapeutic use for joint diseases—which paved the way to clinic application of hyaluronan was a truly remarkable feat. It was an outstanding achievement in the long history of hyaluronan studies. The audience listened with fascination to the talks by Dr. Hascall and others who knew Dr. Balazs intimately, and gave thought to the background of the times in which he was actively involved in scientific studies as well as the dawning of clinic studies on hyaluronan.
Next, homage was offered to the long-time contributions by Drs. Markku Tammi and Raija Tammi (University of Eastern Finland). They left numbers of memorable achievements in the area of research on control of hyaluronan metabolism, thus establishing a base for hyaluronan studies in Europe. Dr. Kirsi Rilla (University of Eastern Finland), who had worked with the Tammis, recalled, with various tender episodes, the mild personality of the couple who were trusted by everyone as well as their devotion toward academic research.
In the session on Application of Hyaluronidase in Medicine (the second day), the topic of a new hyaluronidase identified by Yu Yamaguchi and Hayato Yamamoto drew the participants' interest. They identified mouse homolog of TMEM2 protein that works for the formation of endocarditis cushion of zebra fish, and determined that this molecule is the new membrane protein having hyaluronan degrading activity. This enzyme shows, in terms of primary structure, a similarity with CEMIP/KIAA199 which is also related with hyaluronan catabolism, but differs from CEMIP/KIAA199 in that the recombinant protein has hyaluronidase activity. Japanese researchers are now taking an active role in the studies of hyaluronan catabolism. There is much expectation for their continued activities in the future.
In the session on HA Structure and Metabolism (the third day), Alberto Passi brought up a topic of the natural anti-sense RNA of hyaluronan synthase 2 (Has2-as). He suggested involvement of Has2-as in epigenetic events, in which Has2-as affects the chromatin structure and controls the expression of Has2 genes. It was shown that protein O-GlcNAcylation plays important roles in the control of both promoter activity of Has2-as and functions to stabilize Has2 protein.
Warren Knudson (East Carolina University) et al. established the Has2-overexpressing cartilage cells and analyzed their cartilage protection functions. Has2 overexpression in cartilage cells suppressed both MMP13 expression and reactivity to inflammatory mediators such as IL-1β, suggesting cartilage protection. Although it was a report on preliminary results, they also provided new information that the Has2 overexpression suppressed glycolysis and consequently exhibited cartilage protection.
In the session on HA in Development and Signaling, Natasza Kurpios (Cornell University) et al. showed that hyaluronan matrix plays an important role in the left-right asymmetry during gut development. A primitive gut tube, which generates as a straight tract at the early developmental stage, establishes the left-right asymmetry along the gut development, with the action of Pitx2 transcription factor. Fluorescent images clearly demonstrated that hyaluronan matrix distributed distinctly only on the right half of dorsal mesentery (DM). At this point when hyaluronan matrix is formed, tissues on the right-side DM expands and causes leftward tilt of the primitive gut tube.
In the session on HA in Neurobiology and Neurological Disease (the fourth day), discussion topics were presented on the hyaluronan functions in restoration and regeneration of nerve damage. In the damage of the central nervous system, increased hyaluronan production and degradation can be particularly observed. Larry Sherman et al. clarified that hyaluronan fragments with particular molecular weights generated by the action of hyaluronidase regulate the proliferation and differentiation of neural stem cells via CD44. In relation to this observation, Taasin Srivastava (Oregon Health and Science University) et al. demonstrated that hyaluronan fragments having molecular weight of around 200kDa inhibited the maturity of oligodendrocyte progenitor cells (OPCs) via toll-like receptor 4, and conversely, the suppression of hyaluronan degradation promoted maturity of OPC. These researches clearly showed that hyaluronan of particular size functions to regulate differentiation and maturity of OPCs.
During obesity and diabetes, hyaluronan matrix markedly increases in the brown fat tissue. In the session on HA in Chronic Disease Processes, Dr. Maria Grandoch (Heinrich-Heine-Universität Düsseldorf) et al. reported that the inhibitor of hyaluronan synthesis, 4-Methylumbelliferone (4-MU), significantly reduced the body weight, body fat mass, adipocyte size and the inflammatory reactions in diabetes model mice. They showed that inhibition of hyaluronan synthesis by 4-MU caused increase in glycolytic enzymes, mitochondrial complex I, and respiration of brown adipose tissue. The relations between energy production and sugar metabolism and hyaluronan biosynthesis will be further clarified in the days ahead.
Active discussion took place from 8 a.m. to past 6 p.m. every day during poster sessions and oral presentations before and after lunch. After the afternoon poster session on the fourth day, the conference participants headed to Lake Erie for dinner cruise. The cruise ship Goodtime III that left the lakeside pier steamed leisurely across the lake, passing underneath the historical Lift Bridge over the Cuyahoga River. The participants enjoyed the cruise that guided them through the remembrances of a city that had once thrived for its steel industry, watching the bridges and taking photographs. After sunset, they enjoyed dinner amid gentle breeze, with a night view of the downtown area marked by high-rise buildings in the background.
In the session on HA in Cancer Biology, conducted on the last day of the conference, Kirsi Rilla reported on secretory vesicles covered with hyaluronan. In this topic, she showed that these extracellular vesicles are secreted from diverse cells having high capability of hyaluronan production, such as mesenchymal stem cells and breast cancer cells, and is taken into adjacent cells via hyaluronan receptor CD44. This discovery provided new knowledge that hyaluronan-CD44 interactions not only get involved in cellular-extracellular matrix interactions but also play an important role in the inter-cellular communication via secretory vesicles.
Further, Paraskevi Heldin痴 group (Uppsala University) reported that Has2-as is essential for the control of TGF-β mediated epithelial-mesemchymal transition and functions for the induction of cancer stemness in breast cancer cells.
I chaired the last session entitled HA in Stem Cells, Growth and Differentiation. Presenters reported on dynamic functions of hyaluronan in the control of stem cells as well as in the process of development and differentiation. Notably, Aravind Sivalumar who works with Natasza Kurpios (mentioned earlier) showed that the hyaluronan matrix composed of high molecular hyaluronan and its binding molecule, tumor necrosis factor alpha-inducible protein 6 (Tsg6), is closely related to the regulation of asymmetrical vascularization during the gut tube development. When hyaluronan matrix is formed in the right-side DM, vascular endothelial cells move from right to left side, resulting in the asymmetry of vascularization in DM. This presumably presents an instance that proved very clearly the functions of hyaluronan matrix. Based on this research, he received an award encouraging young investigators.
During this conference several presentations were made on naked mole rat (Heterocephalus glaber), and I would like to touch them briefly. The naked mole rat has a life span nearly 10 times longer than that of mice. Also, it is highly resistant to cancer. This low incidence rate of cancer seems to be related to hyaluronan production. The naked mole rat is known to produce excessive amount of hyaluronan, and is attracting special attention with regard to the antioxidation and anti-tumor effects. Katelyn Cousteils (London Health Sciences Centre) et al. clarified that hyaluronan derivatives having a similar molecular weight as hyaluronan produced in the skin of naked mole rat significantly suppressed the occurrence of skin tumors induced by UVB irradiation, and provided direct evidence for anti-tumor effect of high molecular hyaluronan. Further, Zhonghe Ke et al. generated transgenic mice in which Has2 genes of naked mole rat were introduced, and clarified that high production of hyaluronan in bone marrow induced increase of hematopoietic stem cells through the maintenance of stemness. This discovery suggests the possibility that hyaluronan indirectly plays a role in longevity by regulating stemness.
At the end of the conference, Carol de la Motte delivered a closing speech and expressed words of gratitude to the staff. The conference ended successfully, with standing ovation. Looking over the past conferences, active participation by young researchers was particularly conspicuous this year, together with increased participation of researchers from different research fields. This trend certainly forebodes the advent of new tide of the times. By contrast, I noticed that the number of Japanese participants in the conference has been decreasing. I felt strongly there is an urgent need to raise the standards of hyaluronan studies in Japan.
The next meeting will be held in 2019 in Cardiff, the largest city in Wales, UK.
