PDF(Pubmed)
Abstract：
The objective of this study was to evaluate the feasibility, safety, and effectiveness of intravenous stem cell delivery utilizing ultrasound-targeted microbubble destruction (UTMD) in a rat model of middle cerebral artery occlusion (MCAO), while investigating the underlying mechanisms. Acute cerebral infarction (ACI) was induced surgically in adult rats to create the MCAO rat model. Intravenous injection of SonoVue microbubbles and bone marrow-derived mesenchymal stem cells (BMSC) was performed concurrently, with or without ultrasound targeting the stroke. The animals were divided into four groups: sham-operated group, ACI-MCAO rats treated with phosphate-buffered saline (ACI+PBS), rats receiving intravenous delivery of BMSC expressing green fluorescent protein (GFP-BMSC; ACI+BMSC), and rats receiving intravenous GFP-BMSC with simultaneous UTMD exposure (ACI+BMSC+UTMD). The efficacy of the treatments was assessed by evaluating the animals\' neurological function using the Longa score and examining histopathological changes such as cerebral infarct volume, cerebral edema, and cell apoptosis. A rat cytokine array was utilized to identify the potential cytokines that may be responsible for the therapeutic effect of UTMD-mediated BMSC treatment. Optimal UTMD parameters resulted in an increase in blood-brain barrier (BBB) permeability after 30 min, which returned to baseline 72 h later without causing any residual injury. UTMD application significantly increased the homing of intravenously delivered BMSC, resulting in a 2.2-fold increase in GFP-BMSC cell count on day 3 and a 2.6-fold increase on day 7 compared with intravenous delivery alone. This effect persisted for up to 6 weeks after injection. Intravenous BMSC delivery significantly reduced the volume of cerebral infarct and decreased cerebral edema, leading to a lower Longa score. Furthermore, this effect was further enhanced by UTMD. Acute cerebral infarction induced by MCAO led to elevated matrix metalloproteinase 8 (MMP8) levels in the cerebrospinal fluid, which were significantly reduced following UTMD-mediated BMSC treatment. Ultrasound-targeted microbubble destruction facilitates the migration and homing of BMSC into the brain, possibly by transiently increasing blood-brain barrier (BBB) permeability, thereby improving therapeutic outcomes in an ACI rat model. The observed effect may be partly attributed to modulation of MMP8 levels.Advances in knowledge: UTMD-mediated intravenously delivered BMSC transplantation led to a significant increase in cell homing and reduction of MMP8 levels, resulting in increased therapeutic effect in an acute ischemic cerebral infarction model.
摘要：
这项研究的目的是评估可行性，安全,在大脑中动脉阻塞（MCAO）的大鼠模型中，利用超声靶向微泡破坏（UTMD）进行静脉干细胞递送的有效性，同时调查潜在的机制。在成年大鼠中通过手术诱导急性脑梗死（ACI）以创建MCAO大鼠模型。同时静脉注射SonoVue微泡和骨髓间充质干细胞（BMSC），有或没有针对中风的超声波。将动物分为四组：假手术组，用磷酸盐缓冲盐水（ACI+PBS）处理的ACI-MCAO大鼠，接受静脉内递送表达绿色荧光蛋白的BMSC（GFP-BMSC；ACI+BMSC）的大鼠，和接受静脉内GFP-BMSC同时暴露UTMD(ACI+BMSC+UTMD)的大鼠。通过使用Longa评分评估动物的神经功能并检查组织病理学变化，如脑梗死体积，脑水肿,和细胞凋亡。使用大鼠细胞因子阵列来鉴定可能负责UTMD介导的BMSC治疗的治疗效果的潜在细胞因子。最佳的UTMD参数导致30分钟后血脑屏障（BBB）通透性增加，72小时后恢复到基线，没有造成任何残余伤害。UTMD的应用显着增加了静脉内递送的BMSC的归巢，导致GFP-BMSC细胞计数在第3天增加2.2倍,在第7天增加2.6倍。这种效果在注射后持续长达6周。静脉注射BMSC显著减少脑梗死体积，减轻脑水肿，导致Longa得分较低。此外，UTMD进一步增强了这种效应.MCAO诱导的急性脑梗死导致脑脊液中基质金属蛋白酶8（MMP8）水平升高，在UTMD介导的BMSC治疗后显著降低。超声靶向微泡破坏促进BMSC迁移和归巢进入大脑，可能是通过短暂增加血脑屏障（BBB）通透性，从而改善ACI大鼠模型的治疗结果。观察到的效果可能部分归因于MMP8水平的调节。知识进展：UTMD介导的静脉内递送的BMSC移植导致细胞归巢和MMP8水平降低的显着增加，导致急性缺血性脑梗死模型的治疗效果增加。
