Neurogenic and pericytic plasticity of conditionally immortalized cells derived from renal erythropoietin-producing cells.
Neurogenic and pericytic plasticity of conditionally immortalized cells derived from renal erythropoietin-producing cells.
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DOI：
10.1002/jcp.30677
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发表时间：
2022-05
影响因子：
5.6
通讯作者：
Wenger, Roland H.
中科院分区：
文献类型：
--
作者：
Bapst, Andreas M.;Knopfel, Thomas;Nolan, Karen A.;Imeri, Faik;Schuh, Claus D.;Hall, Andrew M.;Guo, Jia;Katschinski, Doerthe M.;Wenger, Roland H.
在成年哺乳动物中，肾脏是循环促红细胞生成素（Epo）的主要来源，Epo是红细胞生成的主要调节剂。小鼠体内数据表明，间质性肾Epo生成（REP）细胞有多种亚型。为了分析成纤维细胞样REP细胞的分化可塑性，我们使用转基因REP细胞报告小鼠模型来产生条件永生化REP衍生（REPD）细胞系。在非允许条件下，REPD细胞停止增殖并获得干细胞样状态，低氧诱导因子2（HIF-2α），干细胞抗原1（SCA-1）和CD 133表达强烈增强，但α-平滑肌肌动蛋白（αSMA）表达也增强，表明肌纤维母细胞信号传导。这些细胞保持了在体内REP细胞中观察到的Epo表达的“开-关”性质，而其他HIF靶基因显示出更持久的调节。与体内REP细胞一样，体外培养的REPD细胞产生长隧道纳米管（TNT），这些纳米管与内皮血管结构对齐，密集地填充有线粒体，并且在缺氧条件下变得更多。虽然抑制线粒体氧消耗减弱了HIF信号传导，但去除TNT并不影响甚至增强HIF靶基因的表达。除了周细胞，REPD细胞容易分化成神经胶质细胞，但不成脂，软骨，或成骨谱系，与至少一个REP细胞亚群的神经元起源一致。总之，这些结果表明这种独特细胞类型的分化特征的前所未有的组合。在非允许条件下，源自肾Epo生成（REP）细胞的永生化REP细胞衍生（REPD）细胞系停止增殖并获得干细胞样状态，缺氧诱导因子2（HIF-2α）、干细胞抗原1（SCA-1）和CD 133表达增强。与体内REP细胞一样，体外培养的REPD细胞产生与内皮血管结构对齐的长纳米管，密集地填充有线粒体，并且在缺氧条件下变得更多。REPD细胞容易分化成神经胶质细胞，但不是间充质谱系，证实了REP细胞的神经元样特征。
In adult mammals, the kidney is the main source of circulating erythropoietin (Epo), the master regulator of erythropoiesis. In vivo data in mice demonstrated multiple subtypes of interstitial renal Epo‐producing (REP) cells. To analyze the differentiation plasticity of fibroblastoid REP cells, we used a transgenic REP cell reporter mouse model to generate conditionally immortalized REP‐derived (REPD) cell lines. Under nonpermissive conditions, REPD cells ceased from proliferation and acquired a stem cell‐like state, with strongly enhanced hypoxia‐inducible factor 2 (HIF‐2α), stem cell antigen 1 (SCA‐1), and CD133 expression, but also enhanced alpha‐smooth muscle actin (αSMA) expression, indicating myofibroblastic signaling. These cells maintained the “on‐off” nature of Epo expression observed in REP cells in vivo, whereas other HIF target genes showed a more permanent regulation. Like REP cells in vivo, REPD cells cultured in vitro generated long tunneling nanotubes (TNTs) that aligned with endothelial vascular structures, were densely packed with mitochondria and became more numerous under hypoxic conditions. Although inhibition of mitochondrial oxygen consumption blunted HIF signaling, removal of the TNTs did not affect or even enhance the expression of HIF target genes. Apart from pericytes, REPD cells readily differentiated into neuroglia but not adipogenic, chondrogenic, or osteogenic lineages, consistent with a neuronal origin of at least a subpopulation of REP cells. In summary, these results suggest an unprecedented combination of differentiation features of this unique cell type. Conditionally immortalized REP cell‐derived (REPD) cell lines derived from renal Epo‐producing (REP) cells ceased from proliferation and acquired a stem cell‐like state under nonpermissive conditions, with enhanced hypoxia‐inducible factor 2 (HIF‐2α), stem cell antigen 1 (SCA‐1), and CD133 expression. Like REP cells in vivo, REPD cells cultured in vitro generated long nanotubes that aligned with endothelial vascular structures, were densely packed with mitochondria, and became more numerous under hypoxic conditions. REPD cells readily differentiated into neuroglia but not mesenchymal lineages, confirming the neuron‐like features of REP cells.
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影响因子：
41.5
作者：
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