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.