Glucose-6-phosphate dehydrogenase plays a critical role in hypoxia-induced CD133+ progenitor cells self-renewal and stimulates their accumulation in the lungs of pulmonary hypertensive rats
Glucose-6-phosphate dehydrogenase plays a critical role in hypoxia-induced CD133+ progenitor cells self-renewal and stimulates their accumulation in the lungs of pulmonary hypertensive rats
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DOI：
10.1152/ajplung.00303.2013
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发表时间：
2014-10-01
影响因子：
4.9
通讯作者：
Gupte, Sachin A.
中科院分区：
文献类型：
--
作者：
Chettimada, Sukrutha;Joshi, Sachindra Raj;Gupte, Sachin A.
虽然缺氧对大多数细胞类型有害，但它有助于祖细胞的存活，并与人类癌症和肺动脉高压等疾病有关。因此，了解促进祖细胞在缺氧中存活的潜在机制，然后开发新的疗法来阻止它们在缺氧相关的人类疾病中的生长是重要的。在这里，我们证明了在缺氧条件下培养时，促进肿瘤发生和肺动脉高压发展的人CD 133（+）祖细胞的增殖和生长增加。此外，葡萄糖-6-磷酸脱氢酶（G6 PD）活性在缺氧的CD 133（+）细胞中增加了3倍。CD 133（+）细胞的增殖需要G6 PD活性的增加，G6 PD抑制或敲低可使其生长停滞。G6 PD活性上调HIF 1 α、细胞周期蛋白A和磷酸化组蛋白H3的表达，从而促进CD 133（+）细胞去分化和自我更新，并改变细胞周期调控。当CD 133（+）细胞与肺动脉平滑肌细胞（PASMCs）共培养时，G6 PD依赖性H2 O2的产生和PASMCs的释放将CD 133（+）细胞募集到膜上，在那里它们附着并表达平滑肌标志物（α-肌动蛋白和SM 22 α）。在常氧条件下，G6 PD的抑制降低了CD 133（+）细胞中平滑肌标志物的表达，但在缺氧条件下则没有。在体内，在低氧诱导的肺动脉高压大鼠肺血管周围区域，CD 133（+）细胞与G6 PD（+）细胞共定位。最后，脱氢表雄酮抑制肺动脉高压大鼠的G6 PD几乎消除了肺动脉周围CD 133（+）细胞的积聚和闭塞性病变的形成。这些观察结果表明，G6 PD在增加低氧诱导的高血压肺中分化为平滑肌细胞的CD 133（+）细胞存活中起关键作用，并有助于肺动脉高压发展过程中的肺动脉重塑。
Although hypoxia is detrimental to most cell types, it aids survival of progenitor cells and is associated with diseases like cancer and pulmonary hypertension in humans. Therefore, understanding the underlying mechanisms that promote survival of progenitor cells in hypoxia and then developing novel therapies to stop their growth in hypoxia-associated human diseases is important. Here we demonstrate that the proliferation and growth of human CD133(+) progenitor cells, which contribute to tumorigenesis and the development of pulmonary hypertension, are increased when cultured under hypoxic conditions. Furthermore, glucose-6-phosphate dehydrogenase (G6PD) activity was increased threefold in hypoxic CD133(+) cells. The increased G6PD activity was required for CD133(+) cell proliferation, and their growth was arrested by G6PD inhibition or knockdown. G6PD activity upregulated expression of HIF1 alpha, cyclin A, and phospho-histone H3, thereby promoting CD133(+) cell dedifferentiation and self-renewal and altering cell cycle regulation. When CD133(+) cells were cocultured across a porous membrane from pulmonary artery smooth muscle cells (PASMCs), G6PD-dependent H2O2 production and release by PASMCs recruited CD133(+) cells to the membrane, where they attached and expressed smooth muscle markers (alpha-actin and SM22 alpha). Inhibition of G6PD reduced smooth muscle marker expression in CD133(+) cells under normoxia but not hypoxia. In vivo, CD133(+) cells colocalized with G6PD(+) cells in the perivascular region of lungs from rats with hypoxia-induced pulmonary hypertension. Finally, inhibition of G6PD by dehydroepiandrosterone in pulmonary arterial hypertensive rats nearly abolished CD133(+) cell accumulation around pulmonary arteries and the formation of occlusive lesions. These observations suggest G6PD plays a key role in increasing hypoxia-induced CD133(+) cell survival in hypertensive lungs that differentiate to smooth muscle cells and contribute to pulmonary arterial remodeling during development of pulmonary hypertension.