Hypoxic metabolism in human hematopoietic stem cells

Fatih Kocabas, Li Xie, Jingjing Xie, Zhuo Yu, Ralph J. DeBerardinis, Wataru Kimura, SuWannee Thet, Ahmed F. Elshamy, Hesham Abouellail, Shalini Muralidhar, Xiaoye Liu, Chiqi Chen, Hesham A. Sadek, Cheng Cheng Zhang, Junke Zheng

Adult hematopoietic stem cells (HSCs) are maintained in a microenvironment, known as niche in the endosteal regions of the bone marrow. This stem cell niche with low oxygen tension requires HSCs to adopt a unique metabolic profile. We have recently demonstrated that mouse long-term hematopoietic stem cells (LT-HSCs) utilize glycolysis instead of mitochondrial oxidative phosphorylation as their main energy source. However, the metabolic phenotype of human hematopoietic progenitor and stem cells (HPSCs) remains unknown. We show that HPSCs have a similar metabolic phenotype, as shown by high rates of glycolysis, and low rates of oxygen consumption. Fractionation of human mobilized peripheral blood cells based on their metabolic footprint shows that cells with a low mitochondrial potential are highly enriched for HPSCs. Remarkably, low MP cells had much better repopulation ability as compared to high MP cells. Moreover, similar to their murine counterparts, we show that Hif-1α is upregulated in human HPSCs, where it is transcriptionally regulated by Meis1. Finally, we show that Meis1 and its cofactors Pbx1 and HoxA9 play an important role in transcriptional activation of Hif-1α in a cooperative manner. These findings highlight the unique metabolic properties of human HPSCs and the transcriptional network that regulates their metabolic phenotype.