Report: Space Biology research

This article is from a newsletter of “Integral Understanding of life-regulation mechanism from ‘SPACE’ (Living in Space)“, a Grant-in-Aid for Scientific Research on Innovative Areas funded by the Japan Society for the Promotion of Science, in which Ken Takahashi participated as a project member.

Mechanosensing Mechanisms for Sensing Mechanical Stress Including Gravitational Changes

Goal

Bone loss and muscle atrophy occur in the microgravity environment of space. However, it remains poorly understood how cells including bone and muscle cells sense gravity. The purpose of this study was to elucidate how cells sense gravity. The ultimate goal is to understand the mechanism by which living organisms perceive mechanical stimuli, including gravity, at a wide range of levels from cells, tissues, organs, and individuals.

Development/finding

I. Observation of the response of cells to gravity

In order to observe the response of cells to gravity in real-time, we developed a fluorescence microscope system that generates gravity by centrifugal force (picture, Japanese Patent Application No. 2016-043814). By remotely controlling the CMOS camera and LED light source during rotation, we succeeded in imaging changes in cell morphology under gravity. In addition, we are currently developing an inverted centrifugal microscope that is more suitable for observing cultured cells. In the future, we will observe the displacement of intracellular organelles, such as mitochondria, under the load of gravity to elucidate the gravity sensing mechanism of cells.

Picture: Fluorescence microscope system that generates gravity by centrifugal force. A 20× objective lens and a filter for observing green fluorescence were attached to the centrifugal microscope system. Changes in cell morphology in response to rotational stimuli were successfully observed for several tens of minutes.

II. Role of mechanosensitive ion channels in cellular response to gravity

In mesenchymal stem cells, which are expected to be applied to regenerative medicine of bone and myocardium, the activation of a protein called YAP is known to be involved in the differentiation into bone cells. Using mesenchymal stem cells, we have been conducting research to clarify the mechanism by which mesenchymal stem cells sense microgravity by creating a simulated microgravity environment with a clinostat device.

In previous studies, we found that decreased YAP activity may play an important role in the process by which the bone differentiation of mesenchymal stem cells is suppressed in a simulated microgravity environment. We also found that the activation of YAP requires the activation of a protein called protein kinase C (PKC).

Furthermore, we investigated whether the activity of the mechanosensitive ion channel TRPV4 (Transient Receptor Potential Channel V4) is involved in the decrease in YAP activity that mesenchymal cells exhibit to simulated microgravity. As a result, we found that activating TRPV4 with an activator suppresses the decrease in YAP signal activity due to the simulated microgravity environment. On the other hand, when TRPV4 expression in mesenchymal stem cells was suppressed, a decrease in YAP signal activity was observed regardless of the strength of gravity. These results suggest that TRPV4 acts upstream of YAP in the gravity-sensing of mesenchymal stem cells. In the future, we will elucidate whether the mechanism by which mesenchymal stem cells sense gravity and differentiate into bone can be explained by a series of events: activation of TRPV4 channels, PKC, and YAP.

This study was supported by a Grant-in-Aid for Scientific Research on Innovative Areas [No. 15H05936].

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Takahashi Lab at Okayama University uses principles of physiology, cellular and molecular biology, and biophysics. The purpose of the lab is to develop science and medicine by unveiling the mechanisms of diseases through collaborations with scientists, epidemiologists, and corporate alliances. The alliance includes Harvard University, Boston University, Tokyo University of Science, and PD Aerospace, Ltd.