Heart failure is the one of the leading causes of death in the United States. Myocardial infarction (MI) is followed by cardiac remodeling involving extensive fibrosis and which can ultimately progress into heart failure. Previous studies have shown both that both post-MI and post-ischemia reperfusion (I/R), there is a reduction in scar size and improved cardiac function as a result of administration of cortical bone stem cell (CBSC) treatment. We investigated the effects of mouse CBSCs (mCBSC), human CBSCs (hCBSC), mCBSC-derived exosomes and hCBSC-derived exosomes on murine embryonic fibroblast (MEF) migration. Exosome depletion from the CBSC-CM enhanced the reduction in fibroblast migration, implying exosome contents are involved in fibroblast migration. To examine if exosomes decrease fibrotic activation, adult rat ventricular fibroblasts (ARVFs) and adult human cardiac fibroblasts (NHCFs) were treated with TGFβ to activate fibrotic signaling before treatment with mCBSC- and hCBSC-derived exosomes. hCBSC-derived exosomes caused a 100-fold decrease in human fibroblast activation. To further understand the signaling mechanisms regulating the protective decrease in fibrosis, we performed RNA sequencing on the NHCFs after hCBSC-derived exosome treatment. The group treated with both TGFβ and exosomes showed a decrease in small nucleolar RNA (snoRNA), known to be involved with ribosome stability. A 24hr I/R study on mice showed that injection of mCBSCs and mCBSC-derived exosomes into the ischemic region of an infarct had a protective effect against I/R injury. Additionally, we found that mCBSC-derived exosomes recapitulate the effects of CBSC treatment post-I/R, indicating exosomes are partly responsible for CBSC's therapeutic effects.

中文翻译：

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皮质骨干细胞源性外泌体对心肌缺血再灌注和心脏重塑的治疗作用

心力衰竭是美国的主要原因之一。心肌梗塞（MI）之后会发生涉及广泛纤维化的心脏重塑，最终可能进展为心力衰竭。先前的研究表明，在心肌梗死后和缺血再灌注 (I/R) 后，皮质骨干细胞 (CBSC) 治疗可减少疤痕大小并改善心脏功能。我们研究了小鼠 CBSC (mCBSC)、人 CBSC (hCBSC)、mCBSC 衍生的外泌体和 hCBSC 衍生的外泌体对小鼠胚胎成纤维细胞 (MEF) 迁移的影响。CBSC-CM 的外泌体消耗增强了成纤维细胞迁移的减少，这意味着外泌体内容物参与了成纤维细胞迁移。为了检查外泌体是否减少纤维化激活，在用 mCBSC 和 hCBSC 衍生的外泌体处理之前，用 TGFβ 处理成年大鼠心室成纤维细胞 (ARVF) 和成人心脏成纤维细胞 (NHCF)，以激活纤维化信号传导。hCBSC 衍生的外泌体导致人成纤维细胞活化降低 100 倍。为了进一步了解调节纤维化保护性减少的信号机制，我们对 hCBSC 衍生的外泌体处理后的 NHCF 进行了 RNA 测序。同时接受 TGFβ 和外泌体治疗的组显示小核仁 RNA (snoRNA) 减少，已知与核糖体稳定性有关。对小鼠进行的 24 小时 I/R 研究表明，将 mCBSC 和 mCBSC 衍生的外泌体注射到梗塞缺血区域具有针对 I/R 损伤的保护作用。此外，