Transcriptomics analysis reveals molecular alterations underpinning spaceflight dermatology

doi:10.1038/s43856-024-00532-9

. 2024 Jun 11;4(1):106.

doi: 10.1038/s43856-024-00532-9.

Transcriptomics analysis reveals molecular alterations underpinning spaceflight dermatology

Henry Cope^#¹, Jonas Elsborg^#^{2

3}, Samuel Demharter³, J Tyson McDonald⁴, Chiara Wernecke^{5

6}, Hari Parthasarathy^{5

7}, Hriday Unadkat^{5

8}, Mira Chatrathi^{5

9}, Jennifer Claudio^{5

10}, Sigrid Reinsch^{5

11}, Pinar Avci¹², Sara R Zwart¹³, Scott M Smith¹⁴, Martina Heer¹⁵, Masafumi Muratani^{16

17}, Cem Meydan¹⁸, Eliah Overbey¹⁸, Jangkeun Kim¹⁸, Christopher R Chin¹⁸, Jiwoon Park^{18

19}, Jonathan C Schisler²⁰, Christopher E Mason^{18

19}, Nathaniel J Szewczyk^{1

21}, Craig R G Willis²², Amr Salam²³, Afshin Beheshti^{24

25}

Affiliations

¹ School of Medicine, University of Nottingham, Derby, DE22 3DT, UK.
² Department of Energy Conversion and Storage, Technical University of Denmark, 2800, Kongens Lyngby, Denmark.
³ Abzu, Copenhagen, 2150, Denmark.
⁴ Department of Radiation Medicine, School of Medicine, Georgetown University, Washington D.C., WA, 20057, USA.
⁵ NASA GeneLab For High Schools Program (GL4HS), Space Biology Program, NASA Ames Research Center, Moffett Field, CA, USA.
⁶ Department of Aerospace and Geodesy, TUM School of Engineering and Design, Technical University of Munich, Munich, Germany.
⁷ College of Engineering and Haas School of Business, University of California, Berkeley, Berkeley, CA, 94720, USA.
⁸ School of Engineering and Applied Science, Princeton University, Princeton, NJ, 08540, USA.
⁹ College of Letters and Science, University of California, Berkeley, Berkeley, CA, 94720, USA.
¹⁰ Blue Marble Space Institute of Science, Space Biosciences Division, NASA Ames Research Center, Moffett field, CA, USA.
¹¹ Space Biosciences Division, NASA Ames Research Center, Moffett field, CA, USA.
¹² Department of Dermatology and Allergy, University Hospital, LMU Munich, 80337, Munich, Germany.
¹³ University of Texas Medical Branch, Galveston, TX, USA.
¹⁴ Biomedical Research and Environmental Sciences Division, Human Health and Performance Directorate, NASA Johnson Space Center, Houston, TX, 77058, USA.
¹⁵ IU International University of Applied Sciences, Erfurt and University of Bonn, Bonn, Germany.
¹⁶ Transborder Medical Research Center, University of Tsukuba, Ibaraki, 305-8575, Japan.
¹⁷ Department of Genome Biology, Institute of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan.
¹⁸ Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, New York, NY, USA.
¹⁹ Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, 10065, USA.
²⁰ McAllister Heart Institute and Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
²¹ Ohio Musculoskeletal and Neurological Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, 45701, USA.
²² School of Chemistry and Biosciences, Faculty of Life Sciences, University of Bradford, Bradford, BD7 1DP, UK.
²³ St John's Institute of Dermatology, King's College London, Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.
²⁴ Blue Marble Space Institute of Science, Space Biosciences Division, NASA Ames Research Center, Moffett field, CA, USA. afshin.beheshti@nasa.gov.
²⁵ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. afshin.beheshti@nasa.gov.

^# Contributed equally.

PMID: 38862781
PMCID: PMC11166967
DOI: 10.1038/s43856-024-00532-9

Transcriptomics analysis reveals molecular alterations underpinning spaceflight dermatology

Henry Cope et al. Commun Med (Lond). 2024.

. 2024 Jun 11;4(1):106.

doi: 10.1038/s43856-024-00532-9.

Authors

Affiliations

¹ School of Medicine, University of Nottingham, Derby, DE22 3DT, UK.
² Department of Energy Conversion and Storage, Technical University of Denmark, 2800, Kongens Lyngby, Denmark.
³ Abzu, Copenhagen, 2150, Denmark.
⁴ Department of Radiation Medicine, School of Medicine, Georgetown University, Washington D.C., WA, 20057, USA.
⁵ NASA GeneLab For High Schools Program (GL4HS), Space Biology Program, NASA Ames Research Center, Moffett Field, CA, USA.
⁶ Department of Aerospace and Geodesy, TUM School of Engineering and Design, Technical University of Munich, Munich, Germany.
⁷ College of Engineering and Haas School of Business, University of California, Berkeley, Berkeley, CA, 94720, USA.
⁸ School of Engineering and Applied Science, Princeton University, Princeton, NJ, 08540, USA.
⁹ College of Letters and Science, University of California, Berkeley, Berkeley, CA, 94720, USA.
¹⁰ Blue Marble Space Institute of Science, Space Biosciences Division, NASA Ames Research Center, Moffett field, CA, USA.
¹¹ Space Biosciences Division, NASA Ames Research Center, Moffett field, CA, USA.
¹² Department of Dermatology and Allergy, University Hospital, LMU Munich, 80337, Munich, Germany.
¹³ University of Texas Medical Branch, Galveston, TX, USA.
¹⁴ Biomedical Research and Environmental Sciences Division, Human Health and Performance Directorate, NASA Johnson Space Center, Houston, TX, 77058, USA.
¹⁵ IU International University of Applied Sciences, Erfurt and University of Bonn, Bonn, Germany.
¹⁶ Transborder Medical Research Center, University of Tsukuba, Ibaraki, 305-8575, Japan.
¹⁷ Department of Genome Biology, Institute of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan.
¹⁸ Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, New York, NY, USA.
¹⁹ Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, 10065, USA.
²⁰ McAllister Heart Institute and Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
²¹ Ohio Musculoskeletal and Neurological Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, 45701, USA.
²² School of Chemistry and Biosciences, Faculty of Life Sciences, University of Bradford, Bradford, BD7 1DP, UK.
²³ St John's Institute of Dermatology, King's College London, Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.
²⁴ Blue Marble Space Institute of Science, Space Biosciences Division, NASA Ames Research Center, Moffett field, CA, USA. afshin.beheshti@nasa.gov.
²⁵ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. afshin.beheshti@nasa.gov.

^# Contributed equally.

PMID: 38862781
PMCID: PMC11166967
DOI: 10.1038/s43856-024-00532-9

Abstract

Background: Spaceflight poses a unique set of challenges to humans and the hostile spaceflight environment can induce a wide range of increased health risks, including dermatological issues. The biology driving the frequency of skin issues in astronauts is currently not well understood.

Methods: To address this issue, we used a systems biology approach utilizing NASA's Open Science Data Repository (OSDR) on space flown murine transcriptomic datasets focused on the skin, biochemical profiles of 50 NASA astronauts and human transcriptomic datasets generated from blood and hair samples of JAXA astronauts, as well as blood samples obtained from the NASA Twins Study, and skin and blood samples from the first civilian commercial mission, Inspiration4.

Results: Key biological changes related to skin health, DNA damage & repair, and mitochondrial dysregulation are identified as potential drivers for skin health risks during spaceflight. Additionally, a machine learning model is utilized to determine gene pairings associated with spaceflight response in the skin. While we identified spaceflight-induced dysregulation, such as alterations in genes associated with skin barrier function and collagen formation, our results also highlight the remarkable ability for organisms to re-adapt back to Earth via post-flight re-tuning of gene expression.

Conclusion: Our findings can guide future research on developing countermeasures for mitigating spaceflight-associated skin damage.

Plain language summary

Spaceflight is a hostile environment which can lead to health problems in astronauts, including in the skin. It is not currently well understood why these skin problems occur. Here, we analyzed data from the skin of space flown mice and astronauts to try and identify possible explanations for these skin problems. It appears that changes in the activation of genes related to damage to DNA, skin barrier health, and mitochondria (the energy-producing parts of cells) may play a role in these skin problems. Further research will be needed to confirm exactly how these changes influence skin health, which could lead to solutions for preventing and managing such issues in astronauts.

PubMed Disclaimer

Conflict of interest statement

J.E. and S.D. are affiliated with Abzu and Abzu is the developer of the QLattice, the symbolic regression-method used in this work. All other authors have no competing interests.

Figures

**Fig. 1. Global data overview.**
a Breakdown of the rodent datasets used in this study. b Clustering of the most variable genes within the rodent datasets with functional annotation.

**Fig. 2. Differentially expressed genes shared between datasets.**
a An upset plot showing the number of significant (FDR ≤ 0.1) differentially expressed genes (DEGs) in spaceflight versus ground data subsets and the number of overlapping significant DEGs between these data subsets. The colored annotation bar on the left of the plot shows how the original datasets divide into 10 data subsets based on all unique conditions including diet, biological sex and strain. The bar plot on the right of the upset plot shows the number of significant DEGs in each of the 10 data subsets. The bar plot on the top shows the number of intersecting DEGs between combinations of the data subsets, as indicated by the connected dots within the body of the upset plot. Black connecting lines indicate combinations spanning across multiple missions, and other connecting lines are colored according to the annotation bar, based on their shared mission. b A bar plot of significant Gene Ontology Biological Process (GOBP) pathways from significant DEGs shared by any subsets within the MHU-2 mission (i.e., DEGs from the blue bars in panel a).

**Fig. 3. Cross-mission genes involved in rodent skin spaceflight response.**
a A heatmap showing regulatory changes of select cross-mission genes (genes that are significantly (FDR ≤ 0.1) differentially expressed between flight and ground control across multiple missions) within each rodent data subset. b A bar plot showing the GOBP pathways that the full list of cross-mission genes are involved in. c A decision boundary plot of the strongest cross-mission QLattice model using only the expression of two genes as input features to predict the spaceflight status of the all mice in the data. d A decision boundary plot of the second-strongest model across all missions.

**Fig. 4. The profile of the cross-mission genes in astronauts.**
a Heatmap showing log₂ fold-change in orthologs of the rodent skin cross-mission genes in astronaut skin data from the Inspiration4 mission, for different skin layers. b Heatmap showing t-score in orthologs of the rodent skin cross-mission genes in hair follicle samples at different time points from the JAXA HAIR astronaut study.

**Fig. 5. Behavior of the specific genes associated with skin health in astronauts and rodents.**
a The orange (suppressed) and green (enriched) heatmap shows the normalized enrichment score (NES) of curated skin health pathways (full list Supplementary Table 1) that are significant (FDR ≤ 0.05) in at least one rodent subset. The red (upregulated) and blue (downregulated) heatmap shows the t-score for leading edge genes from the significant pathways that are significant (FDR ≤ 0.1) in at least two data subsets. b Heatmap showing log₂ fold-change in orthologs of the genes from Panel a in astronaut skin data from the Inspiration4 mission, for different skin layers. c Heatmap showing t-score in orthologs of the genes from Panel a in hair follicle samples at different time points from the JAXA HAIR astronaut study.

**Fig. 6. DNA damage and repair pathways being regulated in rodents flown to space.**
Heatmap of pathways relating to DNA damage response and repair mechanisms (full list Supplementary Table 1), significant (FDR ≤ 0.05) in at least one data subset.

**Fig. 7. Mitochondrial specific analysis on rodent spaceflight skin tissue.**
a Heatmap of pathways relating to the mitochondria, significant (FDR ≤ 0.05) in at least 1 data subset. b Decision boundary for the 2-gene model related to mitochondrial changes. The model indicates an increased removal of the toxic D2H compound in mitochondria through upregulation of *D2HGDH*, which is less pronounced when *PPP1R3B* expression is suppressed.

**Fig. 8. Astronaut physiological markers compiled from up to 50 astronauts.**
a Specific blood markers which contain data points for pre-launch (L−), flight (FD), and return to Earth (R+). The numbers on the x-axis indicate the number of days for each group. Interim Resistive Exercise Device (iRED) is shown in blue and Advanced Resistive Exercise Device (ARED) is shown in red. b Specific blood markers which contain data points for pre-launch (L−) and return to Earth (R+). c Specific urine markers which contain data points for pre-launch (L−), flight (FD), and return to Earth (R+). The statistics on the data are *p < 0.001 for significantly different from L-45 and ‡p < 0.01 significantly different from ARED.

**Fig. 9. Predicted drug signatures associated with spaceflight response in the skin.**
Predicted drug signatures using the cross-mission genes across each dataset represented by a hierarchically clustered heat map. A positive (red) activation state implies cross-mission gene expression changes are consistent with expression changes observed with the indicated drug from curated causal gene expression relationship studies. A negative (blue) activation state implies the cross-mission gene expression changes are opposite to changes observed with the indicated drug.

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Update of

More than a Feeling: Dermatological Changes Impacted by Spaceflight.
Cope H, Elsborg J, Demharter S, Mcdonald JT, Wernecke C, Parthasarathy H, Unadkat H, Chatrathi M, Claudio J, Reinsch S, Zwart S, Smith S, Heer M, Muratani M, Meydan C, Overbey E, Kim J, Park J, Schisler J, Mason C, Szewczyk N, Willis C, Salam A, Beheshti A. Cope H, et al. Res Sq [Preprint]. 2023 Feb 10:rs.3.rs-2367727. doi: 10.21203/rs.3.rs-2367727/v1. Res Sq. 2023. Update in: Commun Med (Lond). 2024 Jun 11;4(1):106. doi: 10.1038/s43856-024-00532-9. PMID: 36798347 Free PMC article. Updated. Preprint.

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References

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1. Crucian B, et al. Incidence of clinical symptoms during long-duration orbital spaceflight. Int. J. Gen. Med. 2016;9:383–391. doi: 10.2147/IJGM.S114188. - DOI - PMC - PubMed
1. Rooney BV, Crucian BE, Pierson DL, Laudenslager ML, Mehta SK. Herpes Virus Reactivation in Astronauts During Spaceflight and Its Application on Earth. Front. Microbiol. 2019;10:16. doi: 10.3389/fmicb.2019.00016. - DOI - PMC - PubMed
1. Mehta SK, et al. Dermatitis during Spaceflight Associated with HSV-1 Reactivation. Viruses. 2022;14:789. doi: 10.3390/v14040789. - DOI - PMC - PubMed
1. Crucian B, et al. A case of persistent skin rash and rhinitis with immune system dysregulation onboard the International Space Station. J. Allergy Clin. Immunol. Pract. 2016;4:759–762.e8. doi: 10.1016/j.jaip.2015.12.021. - DOI - PubMed

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[1] Afshinnekoo E, et al. Fundamental Biological Features of Spaceflight: Advancing the Field to Enable Deep-Space Exploration. Cell. 2020;183:1162–1184. doi: 10.1016/j.cell.2020.10.050. - DOI - PMC - PubMed

[2] Afshinnekoo E, et al. Fundamental Biological Features of Spaceflight: Advancing the Field to Enable Deep-Space Exploration. Cell. 2020;183:1162–1184. doi: 10.1016/j.cell.2020.10.050. - DOI - PMC - PubMed

[3] Crucian B, et al. Incidence of clinical symptoms during long-duration orbital spaceflight. Int. J. Gen. Med. 2016;9:383–391. doi: 10.2147/IJGM.S114188. - DOI - PMC - PubMed

[4] Crucian B, et al. Incidence of clinical symptoms during long-duration orbital spaceflight. Int. J. Gen. Med. 2016;9:383–391. doi: 10.2147/IJGM.S114188. - DOI - PMC - PubMed

[5] Rooney BV, Crucian BE, Pierson DL, Laudenslager ML, Mehta SK. Herpes Virus Reactivation in Astronauts During Spaceflight and Its Application on Earth. Front. Microbiol. 2019;10:16. doi: 10.3389/fmicb.2019.00016. - DOI - PMC - PubMed

[6] Rooney BV, Crucian BE, Pierson DL, Laudenslager ML, Mehta SK. Herpes Virus Reactivation in Astronauts During Spaceflight and Its Application on Earth. Front. Microbiol. 2019;10:16. doi: 10.3389/fmicb.2019.00016. - DOI - PMC - PubMed

[7] Mehta SK, et al. Dermatitis during Spaceflight Associated with HSV-1 Reactivation. Viruses. 2022;14:789. doi: 10.3390/v14040789. - DOI - PMC - PubMed

[8] Mehta SK, et al. Dermatitis during Spaceflight Associated with HSV-1 Reactivation. Viruses. 2022;14:789. doi: 10.3390/v14040789. - DOI - PMC - PubMed

[9] Crucian B, et al. A case of persistent skin rash and rhinitis with immune system dysregulation onboard the International Space Station. J. Allergy Clin. Immunol. Pract. 2016;4:759–762.e8. doi: 10.1016/j.jaip.2015.12.021. - DOI - PubMed

[10] Crucian B, et al. A case of persistent skin rash and rhinitis with immune system dysregulation onboard the International Space Station. J. Allergy Clin. Immunol. Pract. 2016;4:759–762.e8. doi: 10.1016/j.jaip.2015.12.021. - DOI - PubMed

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Transcriptomics analysis reveals molecular alterations underpinning spaceflight dermatology

Affiliations

Transcriptomics analysis reveals molecular alterations underpinning spaceflight dermatology

Authors

Affiliations

Abstract

Plain language summary

Conflict of interest statement

Figures

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References

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Abstract

Plain language summary

Conflict of interest statement

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