Abstract
The regulation of oxygen (O2) levels is crucial in embryogenesis and adult life, as O2 controls a multitude of key cellular functions. Low oxygen levels (hypoxia) are relevant for tissue physiology as they are integral to adequate metabolism regulation and cell fate. Hence, the hypoxia response is of utmost importance for cell, organ and organism function and is dependent on the hypoxia-inducible factor (HIF) pathway. HIF pathway activity is strictly regulated by the family of oxygen-sensitive HIF prolyl hydroxylase domain (PHD) proteins. Physiologic hypoxia is a hallmark of the hematopoietic stem cell (HSC) niche in the bone marrow. This niche facilitates HSC quiescence and survival. The present review focuses on current knowledge and the many open questions regarding the impact of PHDs/HIFs and other proteins of the hypoxia pathway on the HSC niche and on normal and malignant hematopoiesis.
Highlights
Hematopoietic Stem Cells in the Hypoxic Bone Marrow EnvironmentHematopoiesis relies on hematopoietic stem cells (HSCs), a rare cell population in the bone marrow [1]
Quiescent HSCs reside within a specialized microenvironment of the bone marrow (BM), whereby HSCs are located in close vicinity to endothelial cells (ECs) [7,8], perivascular cells [7], mesenchymal stem cells [9] and megakaryocytes [10,11], which are all considered as the BM niche
Since the discovery of hypoxia-inducible factor (HIF) more than 25 years ago, numerous studies have described the influence of hypoxia and hypoxia response pathway proteins in various physiological and pathological processes
Summary
Hematopoiesis (i.e., the generation of blood cells) relies on hematopoietic stem cells (HSCs), a rare cell population in the bone marrow [1]. The present review emphasizes recent advances in the role of the hypoxia response in HSPC metabolism and function as well as in the crosstalk between HSPCs and the BM niche. We here review these aspects both in the context of normal hematopoiesis/normal HSCs and hematological malignancies/leukemic stem cells (LSCs)
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