Intracoronary and retrograde coronary venous myocardial delivery of adipose-derived stem cells in swine infarction lead to transient myocardial trapping with predominant pulmonary redistribution.
Intracoronary and retrograde coronary venous myocardial delivery of adipose-derived stem cells in swine infarction lead to transient myocardial trapping with predominant pulmonary redistribution.
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DOI：
10.1002/ccd.24659
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发表时间：
2014-01-01
影响因子：
2.3
通讯作者：
March, Keith L.
中科院分区：
文献类型：
--
作者：
Hong, Soon Jun;Hou, Dongming;Brinton, Todd J.;Johnstone, Brian;Feng, Dongni;Rogers, Pamela;Fearon, William F.;Yock, Paul;March, Keith L.
关键词：
研究脂肪源性干细胞（ASC）的比较命运及其对冠状动脉微循环的影响，无论是逆行冠状动脉静脉或动脉输送。已提出将ASC局部递送至心脏作为限制心肌梗死程度的实用方法。间充质干细胞对心脏作用的小鼠模型也显示了全身（静脉内）递送的显著益处，这引发了关于局部递送优势的问题。目前还没有研究说明局部递送至心肌后，在大型动物模型中ASC的心肌与全身分布的程度。在最初的实验中，评估了ASC递送对正常猪的冠状动脉循环的剂量依赖性影响，以建立冠状动脉内递送的可耐受ASC剂量范围。在一组后续实验中，通过球囊闭塞近端左前降支（LAD）动脉，然后在AMI后6天通过冠状动脉内（IC）或逆行冠状静脉（RCV）输注107个111铟标记的自体ASC，形成前壁急性心肌梗死（AMI）。在处死前测量微循环阻力（IMR）和冠状动脉血流储备（CFR）的指数，以在细胞递送后1或24小时收集组织用于分析。IC递送猪ASC至正常心肌的耐受性良好，累积剂量高达14 × 106个细胞（约0.5 × 106个细胞/kg）。有证据表明ASC的微循环捕获：在50 × 106个ASC的单位剂量下，发现在分娩后7天靶LAD分布中的IMR和CFR持续改变，而在10 × 106个ASC下，仅CFR改变。在近期MI的背景下，与RCV递送相比，IC递送在1小时时保留的ASC百分比显著更高（57.2 ± 12.7% vs. 17.9 ± 1.6%，p = 0.037），但这种初始差异在24小时时不明显（22.6 ± 5.5% vs. 18.7 ± 8.6%; p = 0.722）。在这两种方法中，大多数ASC在分娩后24小时重新分布到肺循环。ASC通过任一途径递送至梗死组织后，CFR或IMR无显著差异。通过冠状动脉和静脉途径选择性血管内递送ASC导致类似有限的心肌细胞保留，主要是细胞重新分布到肺。ASC的冠状动脉内递送仅导致短暂的更大的心肌保留，这伴随着在较高剂量下冠状动脉微循环的正常区域的阻塞。通过这两种方法局部递送后细胞的主要肺内定位提示了这样的概念，即ASC的全身递送可能提供类似的有益结果，同时避免意外微循环损害的风险。
To examine the comparative fate of adipose-derived stem cells (ASCs) as well as their impact on coronary microcirculation following either retrograde coronary venous or arterial delivery. Local delivery of ASCs to the heart has been proposed as a practical approach to limiting the extent of myocardial infarction. Mouse models of mesenchymal stem cell effects on the heart have also demonstrated significant benefits from systemic (intravenous) delivery, prompting a question about the advantage of local delivery. There has been no study addressing the extent of myocardial vs. systemic disposition of ASCs in large animal models following local delivery to the myocardium. In an initial experiment, dose-dependent effects of ASC delivery on coronary circulation in normal swine were evaluated to establish a tolerable ASC dosing range for intracoronary delivery. In a set of subsequent experiments, an anterior acute myocardial infarction (AMI) was created by balloon occlusion of the proximal left anterior descending (LAD) artery, followed by either intracoronary (IC) or retrograde coronary venous (RCV) infusion of 107 111Indium-labeled autologous ASCs 6 days following AMI. Indices of microcirculatory resistance (IMR) and coronary flow reserve (CFR) were measured before sacrifices to collect tissues for analysis at 1 or 24 hours after cell delivery. IC delivery of porcine ASCs to normal myocardium was well-tolerated up to a cumulative dose of 14×106 cells (approximately 0.5×106 cells/kg). There was evidence suggesting microcirculatory trapping of ASC: at unit doses of 50×106 ASCs, IMR and CFR were found to be persistently altered in the target LAD distribution at 7 days following delivery, while at 10×106 ASCs, only CFR was altered. In the context of recent MI, a significantly higher percentage of ASCs was retained at 1 hour with IC delivery compared to RCV delivery (57.2 ± 12.7% vs. 17.9 ± 1.6%, p=0.037) but this initial difference was not apparent at 24 hours (22.6 ± 5.5% vs. 18.7 ± 8.6%; p= 0.722). In both approaches, most ASC redistributed to the pulmonary circulation by 24 hours post-delivery. There were no significant differences in CFR or IMR following ASC delivery to infarcted tissue by either route. Selective intravascular delivery of ASC by coronary arterial and venous routes leads to similarly limited myocardial cell retention with predominant redistribution of cells to the lungs. Intracoronary arterial delivery of ASC leads to only transiently greater myocardial retention, which is accompanied by obstruction of normal regions of coronary microcirculation at higher doses. The predominant intrapulmonary localization of cells following local delivery via both methods prompts the notion that systemic delivery of ASC might provide similarly beneficial outcomes while avoiding risks of inadvertent microcirculatory compromise.
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