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Low Oxygen = Better Outlook for ASC-based Therapies?

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Review of “Human Adipose-Derived Stem Cells Expanded Under Ambient Oxygen Concentration Accumulate Oxidative DNA Lesions and Experience Procarcinogenic DNA Replication Stress” from Stem Cells Translational Medicine by Stuart P. Atkinson

A major obstacle to the widespread application of human adult stem cell-mediated therapies is the necessity for large cell numbers. Not only does this imply a huge monetary, labor, and time cost, but an extended time in in vitro culture may damage the functionality, and therefore regenerative value,  of said cells. 

A new Stem Cells Translational Medicine study from the laboratories of Rémy Bétous and Jean Sébastien Hoffmann (Cancer Center of Toulouse, France) set out to assess the impact in vitro culture time has on the highly utile adipose-derived mesenchymal stem cell (ASC). Bétous et al now demonstrate that long-term culture under atmospheric oxygen concentrations (21%) has detrimental effects and suggest that the application of physiological low oxygen concentrations (1%) may give a better outlook for ASC-based therapies [1].

Specifically, the study found higher levels of DNA damage, as measured by detection of the 8-oxoG oxidative DNA lesion and the comet assay, in ASCs maintained for up to ten passages under high (21%) as compared to low (1%) oxygen concentrations (See Figure). ASCs cultured at 21% oxygen also displayed higher levels of DNA replication stress, as evidenced by elevated levels of asymmetric DNA replication sister forks and H2AX signals. Of note, cells passed on these markers of damage and stress to daughter cells, highlighting the accumulation of deleterious events as a mode of time in ex vivo culture, and thereby increasing the likelihood of tumorigenic events.

However, the study found no significant genomic instability as a consequence of deleterious changes during ASC cultivation at 21% oxygen, but instead, highlighted the accumulation of small nucleotide polymorphisms suggestive of a mutational bias toward nucleotide transversion which may lead to impaired genomic stability.

The great new study suggests that low oxygen is definitely the way to go to gain a better outlook for ASC-based therapies. Additionally, the authors also suggest that careful monitoring of markers assayed for in their study may find use as biomarkers for ASC suitability. 

Serum-free and xeno-free conditions are a must for stem cells expansion and application, but will low oxygen levels join the ranks of the new and improved materials and methods employed to bring ASCs “up to code” for human transplantation studies? Stay tuned to the Stem Cells Portal to find out.

References

  1. Bétous R, Renoud M-L, Hoede C, et al. Human Adipose-Derived Stem Cells Expanded Under Ambient Oxygen Concentration Accumulate Oxidative DNA Lesions and Experience Procarcinogenic DNA Replication Stress. STEM CELLS Translational Medicine 2017;6:68-76.