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Lower Oxygen Levels Provide a Boost For T-Cell Therapies

Review of “Physioxia enhances T‐cell development ex vivo from human hematopoietic stem and progenitor cells” from STEM CELLS by Stuart P. Atkinson

T lymphocytes originate from bone marrow resident stem cells; however, these all-important immune cells undergo differentiation and maturation in the thymus gland. As oxygen concentrations in the thymus [1] can fall below those observed in the bone marrow or spleen [2-4], researchers led by Hal E. Broxmeyer (Indiana University School of Medicine, Indianapolis, IN, USA) recently sought to explore the influence of physiologically relevant oxygen concentrations (≤5% O2, or “physioxia”) on T lymphocyte commitment and development ex vivo. The improved generation of T lymphocytes may impact patients undergoing hematopoietic cell transplantation and the development of emerging T‐cell therapies.

In their new STEM CELLS article [5], Shin et al. now reports that the culture of hematopoietic stem/progenitor cells under conditions of physioxia to mimic the thymic niche and in the presence of the antioxidant ascorbic acid [6] promotes the enhanced production of T lymphocyte progenitor cells and the maturation of T lymphocytes in an ex vivo artificial thymic organoid culture system. Can lower oxygen levels provide a boost for T-lymphocyte-based therapeutic approaches?

Using a previously described non‐xenogeneic serum‐free and feeder‐free suspension culture system [6], the Broxmeyer team established that a physiologically relevant oxygen concentration significantly improved cord blood-derived hematopoietic stem cell commitment and hematopoietic progenitor cell differentiation into T lymphocyte progenitor cells over two weeks. The authors further enhanced hematopoietic progenitor cell differentiation by adding ascorbic acid (vitamin C), a potent reducing and antioxidant agent. 

Encouragingly, the team then discovered that the presence of a physiologically relevant oxygen concentration and ascorbic acid improved the subsequent maturation of T lymphocyte progenitor cells into CD3+ T lymphocytes within artificial thymic organoids formed in the presence of mouse feeder cells over four weeks [7].

This exciting study represents the first description of the positive effect of a physiologically relevant oxygen concentration on T lymphocyte differentiation and maturation in ex vivo culture systems. Notably, the authors state that these stem cell culture refinements can be easily translated to good manufacturing practice-scale, clinics for patients undergoing hematopoietic cell transplantation, and the development of emerging T‐cell therapies. 

For more on how lower oxygen levels may provide a boost for T-lymphocyte-based therapeutic approaches, stay tuned to the Stem Cells Portal!

References

  1. Braun RD, Lanzen JL, Snyder SA, et al., Comparison of tumor and normal tissue oxygen tension measurements using OxyLite or microelectrodes in rodents. American Journal of Physiology-Heart and Circulatory Physiology 2001;280:H2533-H2544.
  2. Huang X, Trinh T, Aljoufi A, et al., Hypoxia Signaling Pathway in Stem Cell Regulation: Good and Evil. Current Stem Cell Reports 2018;4:149-157.
  3. Ceradini DJ, Kulkarni AR, Callaghan MJ, et al., Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nature Medicine 2004;10:858-864.
  4. Spencer JA, Ferraro F, Roussakis E, et al., Direct measurement of local oxygen concentration in the bone marrow of live animals. Nature 2014;508:269-273.
  5. Shin D-Y, Huang X, Gil C-H, et al., Physioxia enhances T-cell development ex vivo from human hematopoietic stem and progenitor cells. STEM CELLS 2020;38:1454-1466.
  6. Huijskens MJAJ, Walczak M, Koller N, et al., Technical Advance: Ascorbic acid induces development of double-positive T cells from human hematopoietic stem cells in the absence of stromal cells. Journal of Leukocyte Biology 2014;96:1165-1175.
  7. Seet CS, He C, Bethune MT, et al., Generation of mature T cells from human hematopoietic stem and progenitor cells in artificial thymic organoids. Nature Methods 2017;14:521-530.