Cardiovascular disease is one of the most devastating health problems in the modern world, with heart failure and hypertension impacting a rising percentage of the aging population. Increased cardiovascular cell and tissue stiffness is a characteristic associated with normal aging as well as a wide range of cardiovascular diseases. Interestingly, astronauts exposed to microgravity also experience aortic stiffening and reduced cardiac function. Thus, understanding the process and cardiac consequences of arterial stiffening in microgravity may provide new insights into the related cardiovascular diseases associated with aging on Earth. This may then lead to new ways to improve cardiovascular health for humans on Earth as well as for astronauts in microgravity. The overall objective of this research project is to utilize organ-on-chip technology to study accelerated cardiovascular aging in microgravity. The researchers will deploy a novel, organ-on-chip model, known as a micro-CVchips, of the human cardiovascular system in which cardiac and arterial structures will be grown from human pluripotent stem cells and linked in a functional, miniature circulatory system. This will allow for the modeling of fluid movement and organoid stiffness in addition to cell and tissue physiology. A set of these micro-CVchips will be sent to the International Space Station (ISS) to experience microgravity, where they will be monitored and manipulated within a robotic laboratory to determine any signs of an accelerated aging process. Finally, the micro-CVchips will be retrieved and examined on Earth with a set of thorough biological tests. These chips will be compared to control chips that remained on Earth, in addition to patient samples obtained from a tissue biobank at Mount Sinai. This project will also be used as a vehicle to teach and inspire local high school students as part of an ongoing collaboration between Mount Sinai and several New York City schools.
This project is supported by 3 scientific objectives. First, a multi-tissue in vitro microfluidic human organoid model of the cardiovascular system will be characterized. This microfluidic system includes separate cardiac and arterial organoid compartments linked in an endothelialized circulatory system. It will be capable of autonomous cardiac driven flow and arterial driven fluidic resistance changes, allowing it to model arterial stiffening and associated cardiac diastolic dysfunction. Second, a set of the micro-CVchips will be sent to the ISS to experience extended microgravity. Tests for phenotype markers of arterial stiffening and diastolic cardiac dysfunction will be made on board the ISS using an innovative robotic pressure control and video system for near-real-time terrestrial monitoring. This will be combined with post-flight histology studies. Finally, the post-flight analysis of the samples returned from the ISS will be compared to control samples maintained on Earth through numerous molecular biology techniques in order to identify novel disease biomarkers and pathways. The data from the micro-CVchip will also be compared to data obtained from patient samples obtained through the Mount Sinai Cardiovascular Biorepository and 'Omics Facility in order to evaluate the strengths and limitations of the new in vitro model of cardiovascular aging.
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.
