Improving Leukocyte Recovery Through Physiologically Relevant Oxygen Expansion after Hematopoietic Stem Cell Transplantation
Rapid recovery of lymphocytes post hematopoietic stem cell transplantation (HCT) is correlated with positive patient outcome in treatments of hematologic disease. Few effective clinical therapies exist to enhance lymphocyte recovery, indicating a clear unmet need. Ex vivo expansion of umbilical cord blood (CB) cells is an FDA approved therapy to increase recovery of critical hematopoietic cells such as neutrophils and platelets after HCT; however, its impact on lymphocytes remains uncertain. Expansion under physiological oxygen conditions (1-14% O2) results in increased lymphoid-biased RNA levels and lymphocyte progenitor cell numbers. Therefore, I hypothesized that expansion under physiologically relevant oxygen conditions would increase lymphoid progenitor cell numbers and improve lymphocyte recovery post HCT. Both human and murine lymphocyte progenitor cell number or frequency does not significantly change with acute exposure to variable oxygen tension. After murine hematopoietic stem and progenitor cells (HSPCs) were expanded for 7 days, expansion in lower oxygen tensions resulted in decreased overall proliferation but higher proportions of HSPCs compared to higher oxygen cultures. In transplantation models, when analyzed as a ratio of transplanted cells, mice transplanted with HSPCs expanded at 1% O2 exhibited increased donor-derived natural killer cell frequencies at weeks 1 and 10, as well as increased CD4+ and dendritic cell frequencies at week 5 post HCT in the peripheral blood (PB) compared to transplantation with 21% O2 expanded HSPCs. Transplantation with equal numbers of 1% O2 and 21% O2 expanded cells resulted in decreased immune cell recovery in the 21% O2 cohort, indicating reduced function. Transcriptomic analysis revealed differential mitochondrial gene expression in lymphocyte progenitors expanded under 1% O2 compared to 21% O2; these differences were not observed in other progenitor cell populations. Together, these data indicate that low oxygen expansion results in a lymphocyte progenitor cell population that is distinct from lymphocyte progenitors cultured at higher oxygen tensions. This produces a donor graft with increased functionality and more enhanced capability to reconstitute the hematopoietic system post transplantation.
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