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A bit of air please...

...or how small amounts of oxygen contribute to the preservation of lymphocyte progenitors in humans. In an article published in Cell Reports, researchers from LSHL (IRCM) shared new findings on the role of hypoxia in human lymphocyte differentiation.

Published on 19 November 2019

Lymphopoiesis describes the molecular and cellular processes involved in the production of the immune system's lymphocytes, that is, the T lymphocytes, B lymphocytes and natural killer (NK) cells.

In adult humans, lymphopoiesis occurs in the bone marrow for B lymphocytes and NK cells, and in the thymus for T lymphocytes. These lymphocyte production sites are considered to be "hypoxic", with low oxygen levels ranging from 0.1 to 5%. Naturally thus, the lymphocyte progenitor cells evolve in that hypoxic environment. However, to study or manipulate these rare cells, furthermore highly sensitive to microenvironmental signals, researchers place them habitually in Petri dishes, where the oxygen concentration is that of the atmosphere, closer to 21%.

That oxygen level, "hyperoxic" for the progenitor cells, is a limit to the study of their properties or their possible contributions to therapeutic goals.

Oxygenation is a key regulator of cellular physiology. Indeed, William Kaelin, Peter Ratcliffe and Gregg Semenza received the 2019 Nobel Prize for their description of how cells adapt to the variable oxygen levels within the body. Their work opened new therapeutic horizons notably in cancer and anemia.

Researchers from IRCM's Laboratory of Hematopoietic Stem Cells and Leukemia (LSHL) recently published a manuscript in Cell Reports describing their study to, on one hand, analyze the effect of hypoxia on human lymphocyte production and, on the other, determine the experimental conditions necessary for the maintenance of the functional properties of human lymphoid progenitors when manipulated ex vivo.

The team worked on human lymphoid progenitor cells isolated by flow cytometry from umbilical cord blood. They used an oxygen level controller to culture these cells in ideal hypoxic concentrations as well as in normal oxygen levels. Functional studies and molecular analyses demonstrated the key role of hypoxia in the regulation of the metabolism of lymphoid progenitor cells and in the maintenance of their ability to produce lymphocytes, both in culture and in in vivo mouse models. Furthermore, the team showed the essential involvement of specific hypoxia-induced proteins (called HIF for hypoxia inducible factors) in the lymphoid identities of these progenitor cells. The results published by the LSHL team are of interest for the development of gene and cell therapy protocols in bone marrow transplants and immune deficiency treatments.

Their work, largely enabled by IRCM's technological platforms, sheds new light on the role of hypoxia in human lymphocyte development and may help surmount obstacles in the use of lymphoid progenitor cells as therapies.

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