Department of Cardiology, Affiliated Hospital of Yangzhou University, Yangzhou City, People's Republic of China.
Department of Cardiology, Drum Tower Hospital, Nanjing University Medical School, Nanjing City, People's Republic of China.
Stem Cells Dev. 2020 Oct 15;29(20):1331-1345. doi: 10.1089/scd.2019.0264. Epub 2020 Aug 27.
Inflammatory response regulation is a mechanism through which human umbilical cord mesenchymal stem cells (HUCMSCs) improve myocardial ischemia reperfusion injury (IRI); however, the timing of HUCMSC delivery to achieve maximum effectiveness is controversial. To investigate the effects of HUCMSC delivery on the acute inflammatory stage of IRI, we transplanted HUCMSCs or HUCMSCs with cyclosporin A (CsA) through the coronary artery simultaneously during ischemia reperfusion in pigs. Ferumoxytol-labeled HUCMSCs (HUCMSC), HUCMSCs with cyclosporin A (HUCMSC+CsA), and PBS (control) groups were investigated to evaluate the homing of transplanted cells and changes in infarct features, cardiac activity, and inflammatory response at three time points post-transplantation. Animals were sacrificed 2 weeks later for histological analysis of the hearts. We detected Prussian blue-dyed granules distributed around T lymphocyte clusters in the infarct area in the HUCMSC group. Infarct size and collagen deposition in the infarct area were lower in the HUCMSC group than in the control and HUCMSC+CsA groups. Cardiac function was mildly impaired in both the control and HUCMSC groups, whereas added CsA had a more severe impact. The levels of proinflammatory markers were lower in the HUCMSC group than in the control group at 24-h follow-up, and the difference was more significant after adding CsA. There were more CD3 T lymphocytes and Foxp3 Tregs in the HUCMSC group infarct area than in the other two groups. Proliferation rate of T lymphocytes was higher in the HUCMSC group than in the other two groups. Indirect co-culture experiments in vitro showed that MSCs promoted the generation of CD4CD25 Foxp3Tregs through a paracrine mechanism. These results indicate that immediate intracoronary delivery of HUCMSCs after ischemia reperfusion can reduce acute myocardial IRI and promote myocardial repair, mainly through T lymphocyte interactions to regulate the intense inflammatory response during the acute inflammatory stage.
炎症反应调节是人类脐带来源的间充质干细胞（HUCMSCs）改善心肌缺血再灌注损伤（IRI）的机制；然而，HUCMSC 输送以达到最大效果的时间仍存在争议。为了研究 HUCMSC 移植对 IRI 急性炎症期的影响，我们在猪的缺血再灌注期间通过冠状动脉同时移植 HUCMSCs 或环孢素 A（CsA）处理的 HUCMSCs。使用铁氧体标记的 HUCMSCs（HUCMSC）、环孢素 A 处理的 HUCMSCs（HUCMSC+CsA）和磷酸盐缓冲液（PBS，对照组）来评估移植细胞的归巢以及移植后三个时间点梗死特征、心脏活动和炎症反应的变化。两周后处死动物，对心脏进行组织学分析。我们在 HUCMSC 组中检测到普鲁士蓝染色的颗粒分布在 T 淋巴细胞簇周围的梗死区。与对照组和 HUCMSC+CsA 组相比，HUCMSC 组的梗死面积和梗死区胶原沉积减少。对照组和 HUCMSC 组的心脏功能轻度受损，而加入 CsA 后则更严重。与对照组相比，HUCMSC 组在 24 小时随访时促炎标志物水平较低，而加入 CsA 后差异更为显著。与其他两组相比，HUCMSC 组梗死区的 CD3 T 淋巴细胞和 Foxp3 Treg 更多。HUCMSC 组的 T 淋巴细胞增殖率高于其他两组。体外间接共培养实验表明，MSCs 通过旁分泌机制促进 CD4CD25Foxp3Treg 的生成。这些结果表明，缺血再灌注后立即经冠状动脉内输注 HUCMSCs 可减轻急性心肌 IRI 并促进心肌修复，主要通过 T 淋巴细胞相互作用来调节急性炎症期强烈的炎症反应。
