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

Marija Vlaski-Lafarge; Veronique Labat; Alexandra Brandy; Alice Refeyton; Pascale Duchez; Laura Rodriguez; Nyere Gibson; Philippe Brunet de la Grange; Zoran Ivanovic

doi:10.3389/fonc.2020.00713

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

Front Oncol. 2020 May 12:10:713. doi: 10.3389/fonc.2020.00713. eCollection 2020.

Authors

Marija Vlaski-Lafarge^{1

2}, Veronique Labat^{1

2}, Alexandra Brandy^{1

2}, Alice Refeyton^{1

2}, Pascale Duchez^{1

2}, Laura Rodriguez^{1

2}, Nyere Gibson¹, Philippe Brunet de la Grange^{1

2}, Zoran Ivanovic^{1

2}

Affiliations

¹ R&D Department, Etablissement Français du Sang Nouvelle Aquitaine, Bordeaux, France.
² Inserm/U1035, University of Bordeaux, Bordeaux, France.

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^lowCD133⁺CD90⁺CD45RA^- population, highly enriched in hematopoietic stem cells (HSCs), under anoxic, anoxic/aglycemic ("ischemia-like"), or physiological conditions (3% O₂). Results showed, despite a reduction in total cell fold expansion proportionate to the decrease in O₂ 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% O₂. 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 O₂ and O₂/glucose. Our study reveals that this feature is not the consequence of malignant transformation, but an attribute of stemness.

Keywords: bioenergetics; cancer stem cells; hematopoietic stem cells; metabolism; mitochondrial respiration.