通过剪切稀化凝胶延迟递送内皮祖细胞衍生的细胞外囊泡可改善梗死后期的血液动力学。
Delayed delivery of endothelial progenitor cell-derived extracellular vesicles via shear thinning gel improves postinfarct hemodynamics.
机构信息
Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, Pa; Department of Bioengineering, University of Pennsylvania, Philadelphia, Pa.
Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, Pa; Department of Bioengineering, University of Pennsylvania, Philadelphia, Pa.
出版信息
J Thorac Cardiovasc Surg. 2020 May;159(5):1825-1835.e2. doi: 10.1016/j.jtcvs.2019.06.017. Epub 2019 Jun 18.
BACKGROUND
Extracellular vesicles (EVs) are promising therapeutics for cardiovascular disease, but poorly-timed delivery might hinder efficacy. We characterized the time-dependent response to endothelial progenitor cell (EPC)-EVs within an injectable shear-thinning hydrogel (STG+EV) post-myocardial infarction (MI) to identify when an optimal response is achieved.
METHODS
The angiogenic effects of prolonged hypoxia on cell response to EPC-EV therapy and EV uptake affinity were tested in vitro. A rat model of acute MI via left anterior descending artery ligation was created and STG+EV was delivered via intramyocardial injections into the infarct border zone at time points corresponding to phases of post-MI inflammation: 0 hours (immediate), 3 hours (acute inflammation), 4 days (proliferative), and 2 weeks (fibrosis). Hemodynamics 4 weeks post-treatment were compared across treatment and control groups (phosphate buffered saline [PBS], shear-thinning gel). Scar thickness and ventricular diameter were assessed histologically. The primary hemodynamic end point was end systolic elastance. The secondary end point was scar thickness.
RESULTS
EPC-EVs incubated with chronically versus acutely hypoxic human umbilical vein endothelial cells resulted in a 2.56 ± 0.53 versus 1.65 ± 0.15-fold increase (P = .05) in a number of vascular meshes and higher uptake of EVs over 14 hours. End systolic elastance improved with STG+EV therapy at 4 days (0.54 ± 0.08) versus PBS or shear-thinning gel (0.26 ± 0.03 [P = .02]; 0.23 ± 0.02 [P = .01]). Preservation of ventricular diameter (6.20 ± 0.73 mm vs 8.58 ± 0.38 mm [P = .04]; 9.13 ± 0.25 mm [P = .01]) and scar thickness (0.89 ± 0.05 mm vs 0.62 ± 0.03 mm [P < .0001] and 0.58 ± 0.05 mm [P < .0001]) was significantly greater at 4 days, compared wit PBS and shear-thinning gel controls.
CONCLUSIONS
Delivery of STG+EV 4 days post-MI improved left ventricular contractility and preserved global ventricular geometry, compared with controls and immediate therapy post-MI. These findings suggest other cell-derived therapies can be optimized by strategic timing of therapeutic intervention.
背景
细胞外囊泡（EVs）是心血管疾病有前途的治疗方法，但时机不佳可能会阻碍疗效。我们在心肌梗死后（MI）内，对可注射剪切稀化水凝胶（STG+EV）中内皮祖细胞（EPC）-EV 的时间依赖性反应进行了特征描述，以确定何时能达到最佳反应。
方法
在体外测试了延长缺氧对细胞对 EPC-EV 治疗反应和 EV 摄取亲和力的影响。通过左前降支结扎建立大鼠急性 MI 模型，并在 MI 后炎症的各个阶段（0 小时[即刻]、3 小时[急性炎症]、4 天[增殖]和 2 周[纤维化]）通过心肌内注射将 STG+EV 递送至梗死边界区。比较治疗组和对照组（磷酸盐缓冲盐水[PBS]、剪切稀化凝胶）治疗后 4 周的血流动力学。组织学评估瘢痕厚度和心室直径。主要血流动力学终点为收缩末期弹性。次要终点为瘢痕厚度。
结果
与急性低氧相比，慢性低氧培养的 EPC-EVs 导致血管网格数量增加 2.56 ± 0.53 倍，14 小时内 EV 摄取增加 1.65 ± 0.15 倍。STG+EV 治疗在 4 天时改善了收缩末期弹性（0.54 ± 0.08）与 PBS 或剪切稀化凝胶（0.26 ± 0.03[P=0.02]；0.23 ± 0.02[P=0.01]）。与 PBS 和剪切稀化凝胶对照组相比，4 天时心室直径（6.20 ± 0.73 mm 比 8.58 ± 0.38 mm[P=0.04]；9.13 ± 0.25 mm[P=0.01]）和瘢痕厚度（0.89 ± 0.05 mm 比 0.62 ± 0.03 mm[P<0.0001]和 0.58 ± 0.05 mm[P<0.0001]）的保存效果更好。
结论
与 MI 后即刻治疗和对照组相比，MI 后 4 天递送 STG+EV 可改善左心室收缩功能并维持整体心室几何形状。这些发现表明，其他细胞衍生疗法可以通过治疗干预的策略性时机优化。
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