. Background Renovascular disease leads to renal ischemia, hypertension, and eventual kidney failure. Autologous transplantation of adipose tissue–derived mesenchymal stem/stromal cells (MSCs) improves perfusion and oxygenation in stenotic human kidneys, but associated atherosclerosis and hypertension might blunt their effectiveness. We hypothesized that renovascular disease alters the human MSC transcriptome and impairs their reparative potency. Methods MSCs were harvested from subcutaneous abdominal fat of patients with renovascular disease and healthy volunteers (n=3 each), characterized and subsequently injected (5×105/200 μl) into mice 2 weeks after renal artery stenosis or sham surgery (n=6/group). Two weeks later, mice underwent imaging and tissue studies. MSCs from healthy volunteers and in those with renovascular disease were also characterized by mRNA/microRNA (miRNA) sequencing. Based on these, MSC proliferation and mitochondrial damage were assessed in vitro before and after miRNA modulation and in vivo in additional renal artery stenosis mice administered with MSCs from renovascular disease pretreated with miR-378h mimic (n=5) or inhibitor (n=4). Results MSCs engrafted in stenotic mouse kidneys. Healthy volunteer MSCs (but not renovascular disease MSCs) decreased BP, improved serum creatinine levels and stenotic-kidney cortical perfusion and oxygenation, and attenuated peritubular capillary loss, tubular injury, and fibrosis. Genes upregulated in renovascular disease MSCs versus healthy volunteer MSCs were mostly implicated in transcription and cell proliferation, whereas those downregulated encoded mainly mitochondrial proteins. Upregulated miRNAs, including miR-378h, primarily target nuclear-encoded mitochondrial genes, whereas downregulated miRNAs mainly target genes implicated in transcription and cell proliferation. MSC proliferation was similar, but their mitochondrial structure and reparative function both in vivo and in vitro improved after miR-378h inhibition. Conclusions Renovascular disease impaired the reparative capacity of human MSCs, possibly by dysregulating miR-378h that targets mitochondrial genes. Podcast This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2024_08_21_ASN0000000000000440.mp3...

中文翻译：

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人间充质干细胞中的肾血管疾病和线粒体功能障碍


.背景 肾血管疾病导致肾缺血、高血压，并最终导致肾功能衰竭。脂肪组织来源的间充质干细胞/基质细胞 （MSCs） 的自体移植可改善狭窄人类肾脏的灌注和氧合，但相关的动脉粥样硬化和高血压可能会减弱其有效性。我们假设血管疾病会改变人类 MSC 转录组并损害其修复效力。方法 从肾血管疾病患者和健康志愿者 （各 n=3） 的皮下腹部脂肪中采集 MSCs，表征后 2 周肾动脉狭窄或假手术 （n=6/组） 注射 （5×105/200 μl） 到小鼠体内。两周后，小鼠接受影像学和组织研究。来自健康志愿者和肾血管疾病患者的 MSCs 也通过 mRNA/microRNA （miRNA） 测序进行表征。基于这些，在 miRNA 调节前后的体外以及用 miR-378h 模拟物 （n=5） 或抑制剂 （n=4） 预处理的肾血管疾病 MSC 的额外肾动脉狭窄小鼠的体内评估 MSC 的 MSC 增殖和线粒体损伤。结果 MSCs 植入狭窄的小鼠肾脏。健康志愿者 MSC （但不是肾血管疾病 MSCs） 降低了血压，改善了血清肌酐水平和狭窄肾皮质灌注和氧合，并减轻了肾小管周围毛细血管丢失、肾小管损伤和纤维化。与健康志愿者 MSC 相比，肾血管疾病 MSC 中上调的基因主要与转录和细胞增殖有关，而下调的基因主要编码线粒体蛋白。 上调的 miRNA（包括 miR-378h）主要靶向核编码的线粒体基因，而下调的 miRNA 主要靶向与转录和细胞增殖有关的基因。MSC 增殖相似，但在 miR-378h 抑制后，它们的线粒体结构和体内和体外修复功能都有所改善。结论 肾血管疾病损害了人 MSC 的修复能力，可能是由于靶向线粒体基因的 miR-378h 失调。播客 本文包含 https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2024_08_21_ASN0000000000000440.mp3...