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Hypoxic Culturing Of Human Adipose-derived Stem Cells Enhances Cellular Proliferation And Angiogenesis
John Paul Garcia, M.D., Francisco R. Avila, M.D., Ricardo A. Torres, M.D., Karla C. Maita, M.D., Abdullah S. Eldaly, M.D., Brian D. Rinker, M.D., Abba C. Zubair, M.D., Antonio J. Forte, M.D., PhD, Rachel Sarabia-Estrada, DVM, PhD.
Mayo Clinic, Jacksonville, FL, USA.

Purpose: Human adipose-derived stem cells (hADSCs) have received attention lately, because of their ease of harvesting and ability to be substantially multiplied in laboratory cultures. Stem cells are usually cultured under atmospheric conditions; however, preconditioning of stem cells under hypoxic conditions seems to be beneficial given an upregulation of hypoxia derived genes. This systematic review aims to investigate the effect of hypoxia preconditioning and its impact on the proliferation and angiogenic capacity of hADSCs.
Methods: A systematic review was performed by conducting a search in PubMed, Scopus, Embase, and Google Scholar databases from "oldest" through March 22, 2021, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Medical Subject Headings terms "adipose-derived stem cell," "Hypoxia," "cell proliferation," and "angiogenesis" guided our search. Articles written in English, that used experimental models, and which compared a preconditioned group against a control group of human ADSCs with data on proliferation and angiogenic capacity were included.
Results: Our search yielded a total of 321 articles. Eleven articles met our inclusion criteria and were ultimately included in this review. Two studies induced hypoxia by using hypoxia-inducible factor-1 alpha stabilizing agents, dimethyloxalylglycine and deferoxamine. The remaining studies reached hypoxia by manipulating oxygen tension in the atmosphere around the cells. Although 1 article indicated cell proliferation inhibition, the remaining 10 reported enhanced proliferation and a faster population doubling rate in preconditioned groups compared to controls. All articles showed consistent findings of enhanced angiogenic capacity of human ADSCs after hypoxia preconditioning. Angiogenic capacity was measured via matrigel tube-forming assay. Four articles conducted in-vivo studies to correlate their in-vitro findings, which proved to be consistent throughout both scenarios.
Conclusion: Based on the included studies, growing cells in a hypoxic condition is a more natural process, thus culturing human adipose-derived stem cells under hypoxic conditions may have a beneficial role on regenerative medicine. Benefits include the upregulation of hypoxia-inducible factor-1 alpha, which in turn enhances cell proliferation, with a faster population doubling rate and increases secretion of multiple angiogenic growth factors, which enhance the capability for angiogenesis.


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