比较骨髓间充质干细胞与骨髓间充质干细胞外泌体在与抗纤维化药物联合应用于高血压小鼠时的肾保护作用。
Comparing the renoprotective effects of BM-MSCs versus BM-MSC-exosomes, when combined with an anti-fibrotic drug, in hypertensive mice.
机构信息
Cardiovascular Disease Program, Monash Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia.
Cardiovascular Disease Program, Monash Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia; Stem Cells and Development Program, Monash Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia.
出版信息
Biomed Pharmacother. 2021 Dec;144:112256. doi: 10.1016/j.biopha.2021.112256. Epub 2021 Oct 1.
Fibrosis, a hallmark of chronic kidney disease (CKD), impairs the viability of human bone marrow derived-mesenchymal stromal cells (BM-MSCs) post-transplantation. To address this, we demonstrated that combining BM-MSCs with the anti-fibrotic drug, serelaxin (RLX), enhanced BM-MSC-induced renoprotection in preclinical CKD models. Given the increased interest and manufacturing advantages to using stem cell-derived exosomes (EXO) as therapeutics, this study determined whether RLX could enhance the therapeutic efficacy of BM-MSC-EXO, and compared the renoprotective effects of RLX and BM-MSC-EXO versus RLX and BM-MSCs in mice with hypertensive CKD. Adult male C57BL/6 mice were uninephrectomised, received deoxycorticosterone acetate and given saline to drink (1K/DOCA/salt) for 21 days. Control mice were uninephrectomised and given normal drinking water for the same time-period. Subgroups of 1K/DOCA/salt-hypertensive mice were then treated with either RLX (0.5 mg/kg/day) or BM-MSC-EXO (25 μg/mouse; equivalent to 1-2 × 10 BM-MSCs/mouse) alone; combinations of RLX and BM-MSC-EXO or BM-MSCs (1 × 10/mouse); or the mineralocorticoid receptor antagonist, spironolactone (20 mg/kg/day), from days 14-21. 1K/DOCA/salt-hypertensive mice developed kidney tubular damage, inflammation and fibrosis, and impaired kidney function 21 days post-injury. Whilst RLX alone attenuated the 1K/DOCA/salt-induced fibrosis, BM-MSC-EXO alone only diminished measures of tissue inflammation post-treatment. Comparatively, the combined effects of RLX and BM-MSC-EXO or BM-MSCs demonstrated similar anti-fibrotic efficacy, but RLX and BM-MSCs offered broader renoprotection over RLX and/or BM-MSC-EXO, and comparable effects to spironolactone. Only RLX and BM-MSCs, but not RLX and/or BM-MSC-EXO, also attenuated the 1K/DOCA/salt-induced hypertension. Hence, although RLX improved the renoprotective effects of BM-MSC-EXO, combining RLX with BM-MSCs provided a better therapeutic option for hypertensive CKD.
纤维化是慢性肾脏病（CKD）的一个标志，会损害移植后人类骨髓间充质基质细胞（BM-MSCs）的活力。为了解决这个问题，我们证明了将 BM-MSCs 与抗纤维化药物舒血管素（RLX）结合使用可以增强临床前 CKD 模型中 BM-MSC 诱导的肾保护作用。鉴于人们对使用干细胞衍生的外泌体（EXO）作为治疗药物的兴趣增加和制造优势，本研究旨在确定 RLX 是否可以增强 BM-MSC-EXO 的治疗效果，并比较 RLX 和 BM-MSC-EXO 与 RLX 和 BM-MSCs 在患有高血压 CKD 的小鼠中的肾保护作用。成年雄性 C57BL/6 小鼠接受单侧肾切除术，给予醋酸脱氧皮质酮和生理盐水饮用（1K/DOCA/salt）21 天。对照组小鼠接受单侧肾切除术，并在相同时间内给予正常饮用水。然后，将 1K/DOCA/salt-高血压小鼠亚组分别用 RLX（0.5mg/kg/天）或 BM-MSC-EXO（25μg/只；相当于 1-2×10BM-MSCs/只）单独治疗；RLX 和 BM-MSC-EXO 或 BM-MSCs 的组合（1×10/只）；或从第 14 天到第 21 天，用盐皮质激素受体拮抗剂螺内酯（20mg/kg/天）治疗。1K/DOCA/salt-高血压小鼠在损伤后 21 天发生肾小管损伤、炎症和纤维化，并损害肾功能。虽然 RLX 单独可减轻 1K/DOCA/salt 诱导的纤维化，但 BM-MSC-EXO 单独治疗仅在治疗后减少组织炎症的测量值。相比之下，RLX 和 BM-MSC-EXO 或 BM-MSCs 的联合作用显示出相似的抗纤维化效果，但 RLX 和 BM-MSCs 提供了比 RLX 和/或 BM-MSC-EXO 更广泛的肾保护作用，与螺内酯的效果相当。只有 RLX 和 BM-MSCs，而不是 RLX 和/或 BM-MSC-EXO，也减轻了 1K/DOCA/salt 诱导的高血压。因此，尽管 RLX 改善了 BM-MSC-EXO 的肾保护作用，但 RLX 与 BM-MSCs 联合使用为高血压 CKD 提供了更好的治疗选择。
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