ISS: Cellular Mechanotransduction by Osteoblasts in Microgravity

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Osteoporosis causes bones to become weak and brittle as individuals age and commonly leads to fracture with low forces or a fall. It is well appreciated that weight-bearing exercises are beneficial to the bones and lowers the risk of osteoporosis. In space, microgravity causes a number of physiological changes -- such as heart and bone deconditioning -- and represents a unique experimental environment to test biological hypotheses an environment that speeds up pathological changes. Despite a deep understanding of the outcomes of bone formation and bone loss in bone biomechanics, the mechanism of how applied loading affects the cells and causes bone loss and osteoporosis is not entirely clear. Recent research has suggested that a group of proteins, known as transcription factors, control gene expression in the nucleus of a cell and can be regulated by the stiffness of a cell. Leveraging the unique experimental environment on the International Space Station (ISS), this project will quantify the effect of microgravity on the stiffness of osteoblasts - bone forming cells - and relate this to the signaling that occurs due to key proteins. In addition, the development and function of osteoblasts in microgravity will be compared with and without the addition of mechanical compression in order to see if this returns function to a normal state. Answering these questions will support an increased understanding of how changes in bone loading cause bone loss and osteoporosis, which will in turn support improved prevention and treatment development. The research results will be shared broadly with the public through public talks, seminars, and publications. The PI will collaborate with the Detroit Area Pre-College Engineering Program to develop a bioengineering module for the Saturday Series program for middle school students. This research combines microfluidic devices, cell biology, and bioengineered systems to test the hypothesis that cell mechanics regulates the crosstalk between YAP translocation and Bone Morphogenic Protein (BMP) signaling in the context of osteoblast maturation. The first objective will determine if microgravity affects osteoblast mechanosensitivity by reduceing cell tension and thereby regulationg YAP/BMP crosstalk. The second objective will apply mechanical compression to osteoblasts to see if they recover their mechanosensitivity, as demonstrated by restored YAP/BMP signaling. The project will implement a microfluidic device to autonomously measure the mechanical properties of cells under microgravity and compare these with measurements performed on Earth. The effect of cell tension on BMP signaling and YAP translocation will be measured both on Earth and at the ISS. The ability for mechanical compression to restore BMP signaling of osteoblasts in 3D spheroids under microgravity will also be examined. This work will deliver new bioengineering platforms that will extend current research abilities on the ISS. Significant insights will be gained at the nexus of cell tension, YAP nucleocytoplasmic shuttling, and BMP signaling.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.