Normal Hematopoetic Stem and Progenitor Cells Can Exhibit Metabolic Flexibility Similar to Cancer Cells

Abstract

It is known that cancer stem cells (CSCs) with the largest proliferative capacity survive the anoxic and/or ischemic conditions present inside tumorous tissue. In this study we test whether normal stem cells can survive under the same conditions due to cancer cell-like metabolic adaptations. We cultivated a CD34 + population with a majority of hematopoietic progenitors, and a CD34 + CD38 low CD133 + CD90 + CD45RA − population, highly enriched in hematopoietic stem cells (HSCs), under anoxic, anoxic/aglycemic ("ischemia-like"), or physiological conditions (3% O 2). Results showed, despite a reduction in total cell fold expansion proportionate to the decrease in O 2 concentration; CD34 + cells, aldehyde dehydrogenase-expressing primitive cells, and committed progenitors expanded, even in anoxia. Interestingly, under ischemia-like conditions, stem and CD34 + cell populations are maintained at day-0 level. Cell-cycle analysis further revealed an accumulation of cells in the G0/G1 phase in anoxia or anoxia/aglycemia, with a fraction of cells (∼40%) actively cycling (SG2M phases). Also stem cell analysis showed that in these conditions a long-term Scid Repopulating activity was equal to that found with 3% O 2. In addition stem cells with the highest proliferative capacity were maintained in anoxia/aglycemia and in anoxia. The estimated ATP profile, active mitochondrial content, and succinate accumulation are indicative of anaerobic mitochondrial respiration in both HSCs and CD34 + progenitors under ischemia-like conditions. We demonstrate here that primitive hematopoietic cells show similar metabolic flexibility to CSCs, allowing them to survive a lack of O 2 and O 2 /glucose. Our study reveals that this feature is not the consequence of malignant transformation, but an attribute of stemness.

Putative pathways fueling anaerobic mitochondrial respiration

“…However, based on the shared evolutionary environment and common ancestor, it is likely that eucaryotic cells evolved anaerobic respiratory pathways comparable to those expressed by microbes which use alternative electron acceptors [8, 10-13, 18, 19]. To date, assays performed in an anaerobic environment are typically initiated using media containing atmospheric oxygen levels that deplete over time; thus, yielding incubation conditions that cover an oxygen concentration spectrum, the nadir of which is not measured [20]. Until recently, the ability to study long-term anoxic cell growth has been elusive due to an inability to culture cells ex vivo for extended periods of time in the absence of oxygen.…”