Title: Tendon regeneration and functional enhancement for physical performance via Piezo1-Mkx axis

Abstract:

Tendons and ligaments are tough tissues that precisely connect muscle to bone and bone to bone, respectively. Once damaged; however, they are difficult to heal, and secondary osteoarthritis is known to occur in approximately 60% of cases. However, the development of treatment methods in current medicine has been challenging. One of the reasons for this is that the master transcription factors, the Operation System of our genome, that produce tendons have long been unknown. We created an expression catalog of all 1600 transcription factors and identified Mkx as the central transcription factor for tendons. First, we showed that Mkx could promote the differentiation into tenocytes (tendon cells) from human iPS cells. Using these tenocytes, we could produce tendon-like tissues and show the therapeutic effect of its transplantation in the tendon injury model. Next, we analyzed the potential function of Piezo1, mechano-sensor, and an Mkx upstream activator in tenocytes, by generating the mice in which an active type of Piezo1 was introduced into tenocytes. Surprisingly, in the tendon-specific gain of function Piezo1 mice, jumping ability and Max speed were significantly enhanced. Based on the results in mice, the role of Piezo1 in human athletic performance was tested. In collaboration with the Athrome Consortium, an international athlete genomics organization, we investigated the frequency of active PIEZO1 E756del in Olympic-level sprinters and the general population in Jamaica. Although the analysis is limited to a small number, the results showed that Jamaican sprinters had a significantly increased ratio of functional polymorphism compared to the general population. These discoveries in tendons have allowed us to understand the entire motor function system, contributing healthy society and medical care.

Biography:

Hiroshi Asahara was trained as an Orthopedic Surgeon after graduating from Okayama University Medical School. His career as a researcher led him to be a postdoctoral fellow at Harvard Medical School and a staff scientist at Salk Institute, under Prof. Marc Montminy. Asahara now organizes his own lab as a Professor of Molecular Medicine at The Scripps Research Institute, USA, and as Professor at Tokyo Medical and Dental University, Japan. Based on his unique Systems Biomedicine approaches combining a novel strategy and database, he and his lab are trying to uncover molecular mechanisms of musculoskeletal development and identify the critical pathway to regulate inflammatory diseases, including rheumatoid arthritis.