Hypoxia modulates the undifferentiated phenotype of human renal inner medullary CD133+ progenitors through Oct4/miR-145 balance
Hypoxia modulates the undifferentiated phenotype of human renal inner medullary CD133+ progenitors through Oct4/miR-145 balance
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DOI：
10.1152/ajprenal.00184.2011
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发表时间：
2012-01-01
影响因子：
4.2
通讯作者：
Camussi, Giovanni
中科院分区：
文献类型：
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作者：
Bussolati, Benedetta;Moggio, Aldo;Camussi, Giovanni
Bussolati B、Moggio A、Collino F、Aghemo G、D'Armento G、Grange C、Camussi G。缺氧通过 Oct4/miR-145 平衡调节人肾内髓质 CD133(+) 祖细胞的未分化表型。 Am J Physiol Renal Physiol 302：F116-F128，2012 年。首次发表于 2011 年 9 月 7 日； doi:10.1152/ajprenal.00184.2011.-低氧张力是干细胞微环境的重要组成部分。在啮齿动物中，肾常驻干细胞被描述在乳头中，这是肾脏相对缺氧的区域。在本研究中，我们发现CD133(+)细胞（之前被描述为人类皮质中的肾祖细胞）在肾内髓质中富集，并定位于亨利氏襻和细肢段内。一旦分离，CD133(+)细胞群表达肾胚胎和干相关转录因子，并且能够分化为成熟的肾上皮细胞。当在基质胶内皮下注射到免疫缺陷小鼠体内时，CD133(+)细胞产生不同肾单位段的肾特异性标记物呈阳性的管状结构。乳头状CD133(+)细胞的Oct4A水平和分化潜能高于皮质小管CD133(+)细胞。缺氧能够促进乳头 CD133(+) 祖细胞的未分化表型。缺氧刺激了克隆形成、增殖、血管内皮生长因子合成和 CD133 的表达，而 CD133 的表达反过来又通过上皮分化以及平行的 HIF-1 α 下调而减少。此外，缺氧下调microRNA-145并促进Oct4A的合成。上皮分化增加了 microRNA-145 并降低了 Oct4 水平，表明 Oct4 和 microRNA-145 之间存在平衡。 CD133(+)细胞中MicroRNA-145的过表达诱导Oct4A在蛋白水平上的下调，抑制细胞增殖并刺激终末分化。这项研究强调了低氧微环境在控制肾单位CD133(+)细胞增殖和维持祖细胞表型和干细胞/祖细胞特性中的作用。这种机制可能是维持乳头状区域CD133(+)群体的基础，并且可能参与损伤后的肾再生。
Bussolati B, Moggio A, Collino F, Aghemo G, D'Armento G, Grange C, Camussi G. Hypoxia modulates the undifferentiated phenotype of human renal inner medullary CD133(+) progenitors through Oct4/miR-145 balance. Am J Physiol Renal Physiol 302: F116-F128, 2012. First published September 7, 2011; doi:10.1152/ajprenal.00184.2011.-Low-oxygen tension is an important component of the stem cell microenvironment. In rodents, renal resident stem cells have been described in the papilla, a relatively hypoxic region of the kidney. In the present study, we found that CD133(+) cells, previously described as renal progenitors in the human cortex, were enriched in the renal inner medulla and localized within the Henle's loop and thin limb segments. Once isolated, the CD133(+) cell population expressed renal embryonic and stem-related transcription factors and was able to differentiate into mature renal epithelial cells. When injected subcutaneously in immunodeficient mice within Matrigel, CD133(+) cells generated canalized structures positive for renal specific markers of different nephron segments. Oct4A levels and differentiation potential of papillary CD133(+) cells were higher than those of CD133(+) cells from cortical tubuli. Hypoxia was able to promote the undifferentiated phenotype of CD133(+) progenitors from papilla. Hypoxia stimulated clonogenicity, proliferation, vascular endothelial growth factor synthesis, and expression of CD133 that were in turn reduced by epithelial differentiation with parallel HIF-1 alpha downregulation. In addition, hypoxia downregulated microRNA-145 and promoted the synthesis of Oct4A. Epithelial differentiation increased microRNA-145 and reduced Oct4 level, suggesting a balance between Oct4 and microRNA-145. MicroRNA-145 overexpression in CD133(+) cells induced down-relation of Oct4A at the protein level, inhibited cell proliferation, and stimulated terminal differentiation. This study underlines the role of the hypoxic microenvironment in controlling the proliferation and maintaining a progenitor phenotype and stem/progenitor properties of CD133(+) cells of the nephron. This mechanism may be at the basis of the maintenance of a CD133(+) population in the papillary region and may be involved in renal regeneration after injury.