Eirin Alfonso, Siddiqi Sarosh, Hughes Autumn G, Jiang Yamei, Zhu Xiang-Yang, Kazeminia Sara, Lu Bo, Xing Li, Lu Brandon, Tang Hui, Xue Ailing, Lerman Amir, Textor Stephen C, Lerman Lilach O
Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota.
Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota.
J Am Soc Nephrol. 2024 Nov 1;35(11):1507-1519. doi: 10.1681/ASN.0000000000000440. Epub 2024 Jul 16.
Renovascular disease impairs the capacity of human adipose tissue–derived mesenchymal stem/stromal cells to repair ischemic murine kidneys. miR-378h modulated the capacity of renovascular disease adipose tissue–derived mesenchymal stem/stromal cells to repair ischemic kidneys .
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.
MSCs were harvested from subcutaneous abdominal fat of patients with renovascular disease and healthy volunteers (=3 each), characterized and subsequently injected (5×10/200 l) into mice 2 weeks after renal artery stenosis or sham surgery (=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 before and after miRNA modulation and in additional renal artery stenosis mice administered with MSCs from renovascular disease pretreated with miR-378h mimic (=5) or inhibitor (=4).
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 and improved after miR-378h inhibition.
Renovascular disease impaired the reparative capacity of human MSCs, possibly by dysregulating miR-378h that targets mitochondrial genes.
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肾血管疾病损害了人脂肪组织来源的间充质干/基质细胞修复缺血性小鼠肾脏的能力。miR-378h调节了肾血管疾病脂肪组织来源的间充质干/基质细胞修复缺血性肾脏的能力。
肾血管疾病会导致肾缺血、高血压，并最终导致肾衰竭。自体移植脂肪组织来源的间充质干/基质细胞（MSCs）可改善狭窄人肾脏的灌注和氧合，但相关的动脉粥样硬化和高血压可能会削弱其有效性。我们假设肾血管疾病会改变人MSCs的转录组并损害其修复能力。
从肾血管疾病患者和健康志愿者（每组n = 3）的腹部皮下脂肪中采集MSCs，进行特征鉴定，随后在肾动脉狭窄或假手术后2周将其（5×10⁶/200 μl）注射到小鼠体内（每组n = 6）。两周后，对小鼠进行成像和组织研究。还通过mRNA/微小RNA（miRNA）测序对健康志愿者和肾血管疾病患者的MSCs进行了特征鉴定。基于此，在miRNA调节前后以及在另外给予用miR-378h模拟物预处理的肾血管疾病患者的MSCs（n = 5）或抑制剂（n = 4）的肾动脉狭窄小鼠中评估了MSC增殖和线粒体损伤。
MSCs植入了狭窄的小鼠肾脏。健康志愿者的MSCs（而非肾血管疾病患者的MSCs）降低了血压，改善了血清肌酐水平以及狭窄肾脏的皮质灌注和氧合，并减轻了肾小管周围毛细血管损失、肾小管损伤和纤维化。与健康志愿者的MSCs相比，肾血管疾病患者的MSCs中上调的基因大多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miRNAs，包括miR-378h，主要靶向核编码的线粒体基因，而下调的miRNAs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抑制后其线粒体结构和修复功能均得到改善。
肾血管疾病损害了人MSCs的修复能力，可能是通过失调靶向线粒体基因的miR-378h来实现的。
