心脏球体细胞治疗衰老大鼠后的心脏和全身年轻化。
Cardiac and systemic rejuvenation after cardiosphere-derived cell therapy in senescent rats.
机构信息
Cedars-Sinai Heart Institute, 8700 Beverly Blvd, Los Angeles, CA 90048, USA.
出版信息
Eur Heart J. 2017 Oct 14;38(39):2957-2967. doi: 10.1093/eurheartj/ehx454.
AIM
The aim is to assess the effects of CDCs on heart structure, function, gene expression, and systemic parameters in aged rats. Diastolic dysfunction is characteristic of aged hearts. Cardiosphere-derived cell (CDC) therapy has exhibited several favourable effects on heart structure and function in humans and in preclinical models; however, the effects of CDCs on aging have not been evaluated.
METHODS AND RESULTS
We compared intra-cardiac injections of neonatal rat CDCs to vehicle (phosphate-buffered saline, PBS) in 21.8 ± 1.6 month-old rats (mean ± standard deviation; n = 23 total). Ten rats 4.1 ± 1.5 months of age comprised a young reference group. Blood, echocardiographic, haemodynamic and treadmill stress tests were performed at baseline in all animals, and 1 month after treatment in old animals. Histology and the transcriptome were assessed after terminal phenotyping. For in vitro studies, human heart progenitors from older donors, or cardiomyocytes from aged rats were exposed to human CDCs or exosomes secreted by CDCs (CDC-XO) from paediatric donors. Transcriptomic analysis revealed that CDCs, but not PBS, recapitulated a youthful pattern of gene expression in the hearts of old animals (85.5% of genes differentially expressed, P < 0.05). Telomeres in heart cells were longer in CDC-transplanted animals (P < 0.0001 vs. PBS). Cardiosphere-derived cells attenuated hypertrophy by echo (P < 0.01); histology confirmed decreases in cardiomyocyte area (P < 0.0001) and myocardial fibrosis (P < 0.05) vs. PBS. Cardiosphere-derived cell injection improved diastolic dysfunction [lower E/A (P < 0.01), E/E' (P = 0.05), end-diastolic pressure-volume relationship (P < 0.05) compared with baseline), and lowered serum brain natriuretic peptide (both P < 0.05 vs. PBS). In CDC-transplanted old rats, exercise capacity increased ∼20% (P < 0.05 vs. baseline), body weight decreased ∼30% less (P = 0.05 vs. PBS) and hair regrowth after shaving was more robust (P < 0.05 vs. PBS). Serum biomarkers of inflammation (IL-10, IL-1b, and IL-6) improved in the CDC group (P < 0.05 for each, all vs. PBS). Young CDCs secrete exosomes which increase telomerase activity, elongate telomere length, and reduce the number of senescent human heart cells in culture.
CONCLUSION
Young CDCs rejuvenate old animals as gauged by cardiac gene expression, heart function, exercise capacity, and systemic biomarkers.
目的
评估心脏细胞（CDC）治疗对老年大鼠心脏结构、功能、基因表达和全身参数的影响。舒张功能障碍是老年心脏的特征。心脏球源性细胞（CDC）治疗已在人体和临床前模型中显示出对心脏结构和功能的多种有益作用；然而，CDC 对衰老的影响尚未得到评估。
方法和结果
我们比较了心肌内注射新生大鼠 CDC 与载体（磷酸盐缓冲盐水，PBS）在 21.8±1.6 月龄大鼠（均数±标准差；共 23 只）中的作用。10 只 4.1±1.5 月龄的大鼠作为年轻参考组。所有动物在基线时进行血液、超声心动图、血流动力学和跑步机应激试验，老年动物在治疗后 1 个月进行。在终末表型后进行组织学和转录组学评估。对于体外研究，来自老年供体的人心脏祖细胞或来自老年大鼠的心肌细胞暴露于来自儿科供体的人 CDC 或由 CDC 分泌的外泌体（CDC-XO）。转录组分析显示，CDC 但不是 PBS，可在老年动物的心脏中再现年轻的基因表达模式（85.5%差异表达基因，P<0.05）。心脏细胞中的端粒在接受 CDC 移植的动物中更长（P<0.0001 与 PBS 相比）。心脏球源性细胞减轻了回声引起的肥大（P<0.01）；组织学证实心肌细胞面积减少（P<0.0001）和心肌纤维化减少（P<0.05 与 PBS 相比）。心脏球源性细胞注射改善了舒张功能障碍[较低的 E/A（P<0.01），E/E'（P=0.05），舒张末期压力-容积关系（P<0.05）与基线相比），并降低了血清脑钠肽（均 P<0.05 与 PBS 相比）。在接受 CDC 移植的老年大鼠中，运动能力增加了约 20%（P<0.05 与基线相比），体重减少了约 30%（P=0.05 与 PBS 相比），剃毛后毛发生长更旺盛（P<0.05 与 PBS 相比）。CDC 组血清炎症标志物（IL-10、IL-1b 和 IL-6）改善（均 P<0.05，与 PBS 相比）。年轻的 CDC 分泌外泌体，可增加端粒酶活性、延长端粒长度，并减少培养中的人衰老心脏细胞数量。
结论
年轻的 CDC 可通过心脏基因表达、心脏功能、运动能力和全身生物标志物来恢复老年动物的活力。
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