Skirball Laboratory for Cardiovascular Cellular Therapeutics, Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA.
Circulation. 2012 Jul 17;126(3):314-24. doi: 10.1161/CIRCULATIONAHA.111.082453. Epub 2012 Jun 9.
Overexpression of stromal cell-derived factor-1 in injured tissue leads to improved end-organ function. In this study, we quantify the local trophic effects of mesenchymal stem cell (MSC) stromal cell-derived factor-1 release on the effects of MSC engraftment in the myocardium after acute myocardial infarction.
Conditional cardiac myocyte CXCR4 (CM-CXCR4) null mice were generated by use of tamoxifen-inducible cardiac-specific cre by crossing CXCR4 floxed with MCM-cre mouse. Studies were performed in littermates with (CM-CXCR4 null) or without (control) tamoxifen injection 3 weeks before acute myocardial infarction. One day after acute myocardial infarction, mice received 100,000 MSC or saline via tail vein. We show α-myosin heavy chain MerCreMer and the MLC-2v promoters are active in cardiac progenitor cells. MSC engraftment in wild-type mice decreased terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling positive CM (-44%, P<0.01), increased cardiac progenitor cell recruitment (100.9%, P<0.01), and increased cardiac myosin-positive area (39%, P<0.05) at 4, 7, and 21 days after acute myocardial infarction, respectively. MSC in wild-type mice resulted in 107.4% (P<0.05) increase in ejection fraction in comparison with 25.9% (P=NS) increase in CM-CXCR4 null mice. These differences occurred despite equivalent increases (16%) in vascular density in response to MSC infusion in wild-type and CM-CXCR4 null mice.
These data demonstrate that the local trophic effects of MSC require cardiac progenitor cell and CM-CXCR4 expression and are mediated by MSC stromal cell-derived factor-1 secretion. Our results further demonstrate and quantify for the first time a specific paracrine mechanism of MSC engraftment. In the absence of CM-CXCR4 expression, there is a significant loss of functional benefit in MSC-mediated repair despite equal increases in vascular density.
基质细胞衍生因子-1 在损伤组织中的过表达可改善终末器官功能。在这项研究中，我们定量分析了间充质干细胞（MSC）基质细胞衍生因子-1 释放的局部营养作用对急性心肌梗死后 MSC 移植在心肌中的作用。
通过使用 tamoxifen 诱导的心脏特异性 cre 通过 CXCR4 floxed 与 MCM-cre 小鼠杂交，生成条件性心肌细胞 CXCR4（CM-CXCR4）缺失小鼠。在急性心肌梗死后 3 周前，通过尾静脉给予同窝仔鼠（CM-CXCR4 缺失）或无（对照） tamoxifen 注射进行研究。急性心肌梗死后 1 天，通过尾静脉给予 10 万个 MSC 或盐水。我们表明，α-肌球蛋白重链 MerCreMer 和 MLC-2v 启动子在心脏祖细胞中活跃。在野生型小鼠中，MSC 移植减少了末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记阳性 CM（-44%，P<0.01），增加了心脏祖细胞募集（100.9%，P<0.01），并增加了心肌肌球蛋白阳性面积（39%，P<0.05），分别在急性心肌梗死后 4、7 和 21 天。与 CM-CXCR4 缺失小鼠的 25.9%（P=NS）相比，MSC 在野生型小鼠中的移植导致射血分数增加 107.4%（P<0.05）。尽管在野生型和 CM-CXCR4 缺失小鼠中，MSC 输注引起的血管密度增加相同（16%），但仍存在这些差异。
这些数据表明，MSC 的局部营养作用需要心脏祖细胞和 CM-CXCR4 的表达，并由 MSC 基质细胞衍生因子-1 分泌介导。我们的结果进一步首次证明并量化了 MSC 移植的特定旁分泌机制。在缺乏 CM-CXCR4 表达的情况下，尽管血管密度增加相同，但 MSC 介导的修复功能获益显著丧失。
