Fate-mapping of erythropoietin-producing cells in mouse models of hypoxaemia and renal tissue remodelling reveals repeated recruitment and persistent functionality.
Fate-mapping of erythropoietin-producing cells in mouse models of hypoxaemia and renal tissue remodelling reveals repeated recruitment and persistent functionality.
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DOI：
10.1111/apha.13768
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发表时间：
2022-03
影响因子：
6.3
通讯作者：
Wenger, Roland H.
中科院分区：
文献类型：
--
作者：
Dahl, Sophie L.;Pfundstein, Svende;Hunkeler, Rico;Dong, Xingtong;Knoepfel, Thomas;Spielmann, Patrick;Scholz, Carsten C.;Nolan, Karen A.;Wenger, Roland H.
皮质髓质交界区的成纤维细胞样肾促红细胞生成素(EPO)产生(REP)细胞“感觉”贫血或低氧血症后血氧含量的下降。EPO在组织缺氧时的突发性转录是短暂的，在纤维化组织重塑过程中丢失，如在慢性肾脏疾病中观察到的那样。这种EPO表达缺失的原因还在争论中。因此，我们验证了REP细胞迁移、丢失和/或分化可能导致EPO抑制的假设。使用一只可以在任何给定时间点永久标记活性REP细胞的报告小鼠，我们分析了在低氧血症和肾组织重塑模型中，REP细胞在最初的低氧招募后的时空命运。在长期的示踪实验中，标记的REP报告细胞既没有死亡、增殖、迁移，也没有转分化为肌成纤维细胞。大约60%的标记细胞在第二次低氧刺激下重新表达EPO。在单侧组织重塑模型中，标记的细胞在肌成纤维细胞标志物可检测到增加之前增殖并停止产生EPO。低氧诱导因子(HIF)稳定剂(FG-4592/roxadustat)治疗可重新诱导受损肾脏先前活跃的REP细胞中EPO的表达，其程度与对侧健康肾脏相似。这些结果不是细胞死亡或分化，而是细胞内在的瞬时抑制EPO转录：在长期休眠后，REP细胞可以被组织缺氧重复招募，在肌纤维组织重塑期间，休眠的REP细胞可以被药物HIF稳定剂有效地拯救，即使在EPO抑制的阶段也显示出持久的REP细胞功能。
Fibroblast‐like renal erythropoietin (Epo) producing (REP) cells of the corticomedullary border region “sense” a decrease in blood oxygen content following anaemia or hypoxaemia. Burst‐like transcription of Epo during tissue hypoxia is transient and is lost during fibrotic tissue remodelling, as observed in chronic kidney disease. The reason for this loss of Epo expression is under debate. Therefore, we tested the hypothesis that REP cell migration, loss and/or differentiation may cause Epo inhibition. Using a reporter mouse that allows permanent labelling of active REP cells at any given time point, we analysed the spatiotemporal fate of REP cells following their initial hypoxic recruitment in models of hypoxaemia and renal tissue remodelling. In long‐term tracing experiments, tagged REP reporter cells neither died, proliferated, migrated nor transdifferentiated into myofibroblasts. Approximately 60% of tagged cells re‐expressed Epo upon a second hypoxic stimulus. In an unilateral model of tissue remodelling, tagged cells proliferated and ceased to produce Epo before a detectable increase in myofibroblast markers. Treatment with a hypoxia‐inducible factor (HIF) stabilizing agent (FG‐4592/roxadustat) re‐induced Epo expression in the previously active REP cells of the damaged kidney to a similar extent as in the contralateral healthy kidney. Rather than cell death or differentiation, these results suggest cell‐intrinsic transient inhibition of Epo transcription: following long‐term dormancy, REP cells can repeatedly be recruited by tissue hypoxia, and during myofibrotic tissue remodelling, dormant REP cells are efficiently rescued by a pharmaceutic HIF stabilizer, demonstrating persistent REP cell functionality even during phases of Epo suppression.
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影响因子：
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通讯作者：
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