In Cell Stem Cell, researchers from the Cedars-Sinai Medical Center have published a review discussing what experiments conducted in space can do for stem cell research and medical research as a whole.
Cells behave differently in microgravity
The gravitational effects of freefalling in orbit are very difficult to properly simulate on Earth, making this the prime reason to conduct cellular research in space. Scientists working with NASA have found that cells cultured in such microgravity don’t need scaffolds to grow in three dimensions [1], but on the other hand, microgravity has been found to cause embryonic stem cells to fail to differentiate and regenerate tissues [3].
Other work conducted aboard the International Space Station (ISS) have found that neural organoids mature more quickly in microgravity [2]. This particular research may be strongly relevant to at least one age-related disease: the cells used in this experiment included dopaminergic neurons that deteriorate in Parkinson’s, and, unexpectedly, they had reduced signs of stress and grew readily even without close intervention. Future studies may model Alzheimer’s disease.
Microgravity’s effects on bone deterioration are well-known [4], and studies on bone-building cells have yielded surprising results. One study found that mice that spent time in space had stem cells that were better able to build bone after returning to Earth [5], which these reviewers describe as a “paradoxical” finding. Meanwhile, human bone marrow stem cells grown under these conditions had half the calcification, cell cycle arrest without the characteristic elements of senescence, and less stiffness of the extracellular matrix [6].
Mechanical forces control how cells grow
Physical forces having effects on cellular workings is known as mechanotransduction, and on Earth, cells are constantly exposed to such forces. For example, cells evolved to have their internal structures (cytoskeletons) handle Earth’s gravity. In its absence, these cytoskeletons grow differently [7]. One key pathway has been identified in this process: the Hippo-Yes-associated protein (YAP) signaling axis, which acutely responds to mechanical forces.
Cardiovascular progenitors grown in space upregulate YAP in a way that suggests increased regeneration [8], and using these progenitors to grow organoids in space creates spheres that are thrice the diameter, and contain roughly twenty times the cells, of Earth-bound organoids grown for the same amount of time, with sharp upregulations in genes related to profliferation and survival [9].
Overall, the research on cells grown in microgravity has discovered a complex combination of reactions, some of which appear to be beneficial and others that are not. The reviewers urge more epigenetic testing on these cells, seeking to discover what particular factors are responsible for these modifications. They also note a lack of immunological studies and studies related to vasculature in organoids, and they hold that deriving iPSCs from astronauts themselves may yield insights.
Engineering applications
The amount of energy needed to bring any payload into space, and bring it back safely, makes orbital manufacturing extraordinarily expensive and significantly increases the cost of any research that might be done there. However, pound for pound, creating functional cells is already one of the most expensive activities on Earth. The reviewers note that 3D printing of organoids, a difficult process on Earth because such things often collapse under their own weight, is far easier under conditions where that isn’t a factor, and bioprinting has been done on the ISS since 2019.
Cardiac organoids aren’t the only ones that can be grown rapidly in space; chondrocytes, the cells responsible for growing cartilage, grow up to twice as fast in microgravity conditions [11]. The reviewers suggest that such accelerated growth may make orbital production of these cells a viable prospect, but they also note that not being grown under Earth conditions may make them unable to properly handle shear stresses when they return here. Other work found that mesenchymal stem cells (MSCs) grown under microgravity secreted more anti-inflammatory factors than Earth-grown cells [12].
The researchers note that this work is in its very earliest stages and that stem cell production in orbit is still being investigated as research initatives rather than as production facilities meant to serve clinical patients. Scaling up these efforts will require significant future work and require the mitigation of serious technical hurdles, such as proper shielding against the intense radiation found outside of Earth’s atmosphere.
However, if these hurdles can be overcome, treating some age-related diseases here on Earth may possibly be done with cells grown in orbit.
Literature
[1] Jogdand, A., Landolina, M., & Chen, Y. (2024). Organs in orbit: how tissue chip technology benefits from microgravity, a perspective. Frontiers in lab on a Chip Technologies, 3, 1356688.
[2] Marotta, D., Ijaz, L., Barbar, L., Nijsure, M., Stein, J., Pirjanian, N., … & Fossati, V. (2024). Effects of microgravity on human iPSC-derived neural organoids on the International Space Station. Stem Cells Translational Medicine, 13(12), 1186-1197.
[3] Blaber, E. A., Finkelstein, H., Dvorochkin, N., Sato, K. Y., Yousuf, R., Burns, B. P., … & Almeida, E. A. (2015). Microgravity reduces the differentiation and regenerative potential of embryonic stem cells. Stem cells and development, 24(22), 2605-2621.
[4] Grimm, D., Grosse, J., Wehland, M., Mann, V., Reseland, J. E., Sundaresan, A., & Corydon, T. J. (2016). The impact of microgravity on bone in humans. Bone, 87, 44-56.
[5] Blaber, E. A., Dvorochkin, N., Torres, M. L., Yousuf, R., Burns, B. P., Globus, R. K., & Almeida, E. A. C. (2014). Mechanical unloading of bone in microgravity reduces mesenchymal and hematopoietic stem cell-mediated tissue regeneration. Stem cell research, 13(2), 181-201.
[6] Bradamante, S., Rivero, D., Barenghi, L., Balsamo, M., Minardi, S. P., Vitali, F., & Cavalieri, D. (2018). SCD–stem cell differentiation toward osteoblast onboard the international space station. Microgravity Science and Technology, 30(5), 713-729.
[7] Wu, X. T., Yang, X., Tian, R., Li, Y. H., Wang, C. Y., Fan, Y. B., & Sun, L. W. (2022). Cells respond to space microgravity through cytoskeleton reorganization. The FASEB Journal, 36(2), e22114.
[8] Camberos, V., Baio, J., Bailey, L., Hasaniya, N., Lopez, L. V., & Kearns-Jonker, M. (2019). Effects of spaceflight and simulated microgravity on YAP1 expression in cardiovascular progenitors: implications for cell-based repair. International Journal of Molecular Sciences, 20(11), 2742.
[9] Rampoldi, A., Forghani, P., Li, D., Hwang, H., Armand, L. C., Fite, J., … & Xu, C. (2022). Space microgravity improves proliferation of human iPSC-derived cardiomyocytes. Stem Cell Reports, 17(10), 2272-2285.
[10] Jeyaraman, M., Ramasubramanian, S., Yadav, S., & Jeyaraman, N. (2024). Exploring New Horizons: Advancements in Cartilage Tissue Engineering Under Space Microgravity. Cureus, 16(8).
[11] Jeyaraman, M., Ramasubramanian, S., Yadav, S., & Jeyaraman, N. (2024). Exploring New Horizons: Advancements in Cartilage Tissue Engineering Under Space Microgravity. Cureus, 16(8).
[12] Huang, P., Russell, A. L., Lefavor, R., Durand, N. C., James, E., Harvey, L., … & Zubair, A. C. (2020). Feasibility, potency, and safety of growing human mesenchymal stem cells in space for clinical application. npj Microgravity, 6(1), 16.
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