Hematopoietic stem and progenitor cells (HSPCs) are exposed to low levels of oxygen in the bone marrow niche, and hypoxia-inducible factors (HIFs) are the main regulators of cellular responses to oxygen variation. Recent studies using conditional knockout mouse models have unveiled a major role for HIF-1α in the maintenance of murine HSCs; however, the role of HIF-2α is still unclear. Here, we show that knockdown of HIF-2α, and to a much lesser extent HIF-1α, impedes the long-term repopulating ability of human CD34(+) umbilical cord blood cells. HIF-2α-deficient HSPCs display increased production of reactive oxygen species (ROS), which subsequently stimulates endoplasmic reticulum (ER) stress and triggers apoptosis by activation of the unfolded-protein-response (UPR) pathway. HIF-2α deregulation also significantly decreased engraftment ability of human acute myeloid leukemia (AML) cells. Overall, our data demonstrate a key role for HIF-2α in the maintenance of human HSPCs and in the survival of primary AML cells.
SummaryIn mouse and human skin, HIF-1a is constitutively expressed in the epidermis, mainly in the basal layer. HIF-1a has been shown to have crucial systemic functions: regulation of kidney erythropoietin production in mice with constitutive HIF-1a epidermal deletion, and hypervascularity following epidermal HIF-1a overexpression. However, its local role in keratinocyte physiology has not been clearly defined. To address the function of HIF-1a in the epidermis, we used the mouse model of HIF-1a knockout targeted to keratinocytes (K14-Cre/Hif1a flox/flox ). These mice had a delayed skin phenotype characterized by skin atrophy and pruritic inflammation, partly mediated by basement membrane disturbances involving laminin-332 (Ln-332) and integrins. We also investigated the relevance of results of studies in mice to human skin using reconstructed epidermis and showed that HIF-1a knockdown in human keratinocytes impairs the formation of a viable reconstructed epidermis. A diminution of keratinocyte growth potential, following HIF-1a silencing, was associated with a decreased expression of Ln-322 and a6 integrin and b1 integrin. Overall, these results indicate a role of HIF-1a in skin homeostasis especially during epidermal aging.
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