Toshio Suda: Hematopoietic Stem Cells in Hypoxic Niche

Hematopoietic Stem Cells in Hypoxic Niche

Toshio Suda, Chiharu Ishikawa, Keiyo Takubo Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, School of Medicine, Keio University, Tokyo, Japan sudato@sc.itc.keio.ac.jp

Hematopoietic stem cells (HSCs) are sustained in a specific microenvironment known as the stem cell niche. Adult HSCs are kept quiescent during the cell cycle in the endosteal niche of the bone marrow (BM). The quiescent state is thought to be a characteristic property for the maintenance of HSCs. Normal HSCs maintain intracellular hypoxia, stabilize the hypoxia-inducible factor-1a (HIF-1a) protein and generate ATP by anaerobic metabolism. In HIF-1a-deficiency, HSCs became metabolically aerobic, lost cell cycle quiescence, and finally exhausted. An increased dose of HIF-1a protein in VHL mutated HSCs and their progenitors induced cell cycle quiescence and accumulation of HSCs in the BM. Restored glycolysis by pyruvate dehydrogenase kinases ameliorated cell cycle quiescence and stem cell capacity. Taken together, HSCs directly utilize the hypoxic microenvironment to maintain their cell cycle by HIF-1a-dependent metabolism. I would like to discuss the similarities of stem cell metabolism to cancer cells in hypoxic niche.