"Our study is novel because it is the first to use human induced pluripotent stem cells to study the effects of spaceflight on human heart function," says senior study author Joseph C. Wu of Stanford University School of Medicine. "Microgravity is an environment that is not very well understood, in terms of its overall effect on the human body, and studies like this could help shed light on how the cells of the body behave in space, especially as the world embarks on more and longer space missions such as going to the moon and Mars."

Past studies have shown that spaceflight induces physiological changes in cardiac function, including reduced heart rate, lowered arterial pressure, and increased cardiac output. But to date, most cardiovascular microgravity physiology studies have been conducted either in non-human models or at tissue, organ, or systemic levels. Relatively little is known about the role of microgravity in influencing human cardiac function at the cellular level.

To address this question, Wu and his collaborators (including graduate student Alexa Wnorowski, former Stanford graduate student Arun Sharma, now a research fellow at Cedars-Sinai in Los Angeles, and former Stanford graduate student turned astronaut Kathleen Rubins) studied human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). They generated hiPSC lines from three individuals by reprogramming blood cells, and then differentiated them into hiPSC-CMs.

Beating hiPSC-CMs were then launched to the International Space Station aboard a SpaceX spacecraft as part of a commercial resupply service mission. Simultaneously, ground control hiPSC-CMs were cultured on Earth for comparison purposes.

Upon return to Earth, space-flown hiPSC-CMs showed normal structure and morphology. However, they did adapt by modifying their beating pattern and calcium recycling patterns.

In addition, the researchers performed RNA sequencing of hiPSC-CMs harvested at 4.5 weeks aboard the International Space Station, and 10 days after returning to Earth. These results showed that 2,635 genes were differentially expressed among flight, post-flight, and ground control samples. Most notably, gene pathways related to mitochondrial function were expressed more in space-flown hiPSC-CMs. A comparison of the samples revealed that hiPSC-CMs adopt a unique gene expression pattern during spaceflight, which reverts to one that is similar to groundside controls upon return to normal gravity.

"We're surprised about how quickly human heart muscle cells are able to adapt to the environment in which they are placed, including microgravity," Wu says. "These studies may provide insight into cellular mechanisms that could benefit astronaut health during long-duration spaceflight, or potentially lay the foundation for new insights into improving heart health on Earth."

According to Wu, limitations of the study include its short duration and the use of 2D cell culture. In future studies, the researchers plan to examine the effects of spaceflight and microgravity using more physiologically relevant hiPSC-derived 3D heart tissues with various cell types, including blood vessel cells. "We also plan to test different treatments on the human heart cells to determine if we can prevent some of the changes the heart cells undergo during spaceflight," Wu says.

This work was supported by the Center for the Advancement of Science in Space (CASIS), a Department of Defense National Defense Science and Engineering Graduate Fellowship (AW), a American Heart Association (AHA) Predoctoral Fellowship, the National Science Foundation Graduate Research Fellowship Program, NIH, a AHA postdoctoral fellowship, a NIH Director's Pioneer Award, the NHLBI Progenitor Cell Biology Consortium, an AHA Grant-in-Aid, Burroughs Wellcome Foundation Innovation in Regulatory Science, and an AHA Established Investigator Award. BioServe Space Technologies and SpaceX were implementation partners.

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Journal Reference:

1. Alexa Wnorowski, Arun Sharma, Haodong Chen, Haodi Wu, Ning-Yi Shao, Nazish Sayed, Chun Liu, Stefanie Countryman, Louis S. Stodieck, Kathleen H. Rubins, Sean M. Wu, Peter H.U. Lee, Joseph C. Wu. Effects of Spaceflight on Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Structure and Function. Stem Cell Reports, 2019; DOI: 10.1016/j.stemcr.2019.10.006