Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom.
Blood. 2013 Sep 5;122(10):1741-5. doi: 10.1182/blood-2013-02-484923. Epub 2013 Jul 26.
Local hypoxia in hematopoietic stem cell (HSC) niches is thought to regulate HSC functions. Hypoxia-inducible factor-1 (Hif-1) and Hif-2 are key mediators of cellular responses to hypoxia. Although oxygen-regulated α-subunits of Hifs, namely Hif-1α and Hif-2α, are closely related, they play overlapping and also distinct functions in nonhematopoietic tissues. Although Hif-1α-deficient HSCs lose their activity on serial transplantation, the role for Hif-2α in cell-autonomous HSC maintenance remains unknown. Here, we demonstrate that constitutive or inducible hematopoiesis-specific Hif-2α deletion does not affect HSC numbers and steady-state hematopoiesis. Furthermore, using serial transplantations and 5-fluorouracil treatment, we demonstrate that HSCs do not require Hif-2α to self-renew and recover after hematopoietic injury. Finally, we show that Hif-1α deletion has no major impact on steady-state maintenance of Hif-2α-deficient HSCs and their ability to repopulate primary recipients, indicating that Hif-1α expression does not account for normal behavior of Hif-2α-deficient HSCs.
造血干细胞（HSC）龛位中的局部缺氧被认为可以调节 HSC 的功能。缺氧诱导因子-1（Hif-1）和 Hif-2 是细胞对缺氧反应的关键介质。尽管氧气调节的 Hif 的α亚基，即 Hif-1α 和 Hif-2α，密切相关，但它们在非造血组织中发挥重叠但又不同的功能。尽管 Hif-1α 缺陷的 HSC 在连续移植中丧失了活性，但 Hif-2α 在细胞自主 HSC 维持中的作用仍不清楚。在这里，我们证明了组成型或诱导性造血特异性 Hif-2α 缺失不会影响 HSC 的数量和稳态造血。此外，我们通过连续移植和 5-氟尿嘧啶处理，证明 HSCs 不需要 Hif-2α 来自我更新并在造血损伤后恢复。最后，我们表明 Hif-1α 缺失对 Hif-2α 缺陷 HSC 的稳态维持及其在原发性受者中重新定植的能力没有重大影响，表明 Hif-1α 表达不能解释 Hif-2α 缺陷 HSC 的正常行为。
