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Background  Accumulating evidence suggests that hypoxic areas in the bone marrow are crucial for maintenance of hematopoietic stem cells (HSCs) by supporting a quiescent state of cell cycle and regulating the transplantation capacity of long-term (LT)-HSCs. In addition, HSCs seem to express a metabolic profile of energy production away from mitochondrial oxidative phosphorylation in favor of glycolysis. At oxygen deprivation, hypoxia inducible factor 1α (HIF-1α) is known to induce glycolytic enzymes as well as suppressing mitochondrial energy production by inducing pyruvate dehydrogenase kinase 1 ( Pdk1 ) in most cell types. It has not been established whether PDK1 is essential for HSC function and mediates hypoxia-adapting functions in HSCs. While the  Pdk  gene family contains four members ( Pdk1-4 ), it was recently shown that  Pdk2  and  Pdk4  have an important role in regulating LT-HSCs.    Principle findings  Here we demonstrate that PDK1 activity is crucial for transplantable HSC function. Whereas  Pdkl ,  Pdk2 , and  Pdk3  transcripts were expressed at higher levels in different subtypes of HSCs compared to differentiated cells, we could not detect any major differences in expression between LT-HSCs and more short-term HSCs and multipotent progenitors. When studying HIF-1α-mediated regulation of  Pdk  activity  in vitro ,  Pdk1  was the most robust target regulated by hypoxia, whereas  Pdk2 ,  Pdk3 , and  Pdk4  were not affected. Contrary, genetic ablation in a cre-inducible  Hif-1α  knockout mouse did not support a link between HIF-1α and  Pdk1 . Silencing of  Pdk1  by shRNA lentiviral gene transfer partially impaired progenitor colony formation  in vitro  and had a strong negative effect on both long-term and short-term engraftment in mice.    Conclusions  Our study demonstrates that PDK1 has broad effects in hematopoiesis and is a critical factor for engraftment of both HSCs and multipotent progenitors upon transplantation to recipient mice. While  Pdk1  was a robust hypoxia-inducible gene mediated by HIF-1α  in vitro , we could not find evidence of any  in vivo  links between  Pdk1  and HIF-1α.

Pyruvate dehydrogenase kinase 1 is essential for transplantable mouse bone marrow hematopoietic stem cell and progenitor function