Combined Reporter Gene PET and Iron Oxide MRI for Monitoring Survival and Localization of Transplanted Cells in the Rat Heart
Combined Reporter Gene PET and Iron Oxide MRI for Monitoring Survival and Localization of Transplanted Cells in the Rat Heart
复制标题
DOI：
10.2967/jnumed.108.060665
复制
发表时间：
2009-07-01
影响因子：
9.3
通讯作者：
Schwaiger, Markus
中科院分区：
文献类型：
--
作者：
Higuchi, Takahiro;Anton, Martina;Schwaiger, Markus
有必要对心脏细胞移植治疗后的细胞植入和存活进行体内监测。本研究评估了联合应用PET和MRI监测细胞移植后细胞植入和存活的可行性和有效性。方法：从脐带血CD34+单个核细胞来源的人内皮祖细胞(HEPC)逆转录病毒转导钠碘转运体(NIS)基因，用I-124-PET进行报告基因成像，并用氧化铁标记后进行MRI显示。3组裸鼠分别于心肌内注射400万个HEPC后第1、3、7天进行影像和组织学分析。结果：体外实验证明，转导后的HEPC能稳定表达功能性NIS蛋白，细胞活性正常。在心肌内移植后的第一天，铁标记和NIS标记的HEPC在MRI上被成功地显示为健康心肌中的区域信号空洞，在PET上被成功地显示为I-124聚集。I-124摄取在第3天减少，第7天检测不到，MRI信号在整个随访期内保持不变。CD31和CD68抗体的组织学分析证实，在注射的第1天，无论是标记的还是非标记的对照移植的HEPC都存在，但在第7天，只有铁负载的巨噬细胞可见。此外，脱氧尿酸-5‘-三磷酸生物素缺口末端标记显示移植部位广泛的细胞凋亡。结论：MRI和PET的结合可以结合心脏的形态信息对移植的HEPC的定位和存活进行成像。虽然铁标记由于死亡细胞释放的铁颗粒的吞噬作用而迅速失去了对细胞活力的特异性，但报告基因的表达提供了关于存活细胞数量的特异性信息。这种多模式方法允许对细胞定位和活性进行补充分析。
There is a need for in vivo monitoring of cell engraftment and survival after cardiac cell transplantation therapy. This study assessed the feasibility and usefulness of combined PET and MRI for monitoring cell engraftment and survival after cell transplantation. Methods: Human endothelial progenitor cells (HEPCs), derived from CD34+ mononuclear cells of umbilical cord blood, were retrovirally transduced with the sodium iodide symporter (NIS) gene for reporter gene imaging by I-124-PET and labeled with iron oxides for visualization by MRI. Imaging and histologic analysis were performed on 3 groups of nude rats on days 1, 3, and 7 after intramyocardial injection of 4 million HEPCs. Results: In vitro studies demonstrated stable expression of functional NIS protein and normal viability of HEPCs after transduction. On day 1, after intramyocardial transplantation, iron-and NIS-labeled HEPCs were visualized successfully on MRI as a regional signal void in the healthy myocardium and on PET as I-124 accumulation. The I-124 uptake decreased on day 3 and was undetectable on day 7, and the MRI signal remained unchanged throughout the follow-up period. Histologic analysis with CD31 and CD68 antibodies confirmed the presence of either labeled or nonlabeled control transplanted HEPCs at the site of injection on day 1 but not on day 7, when only iron-loaded macrophages were seen. Furthermore, deoxyuride-5'-triphosphate biotin nick end labeling showed extensive apoptosis at the site of transplantation. Conclusion: The combination of MRI and PET allows imaging of localization and survival of transplanted HEPCs together with morphologic information about the heart. Although iron labeling rapidly loses specificity for cell viability because of phagocytosis of iron particles released from dead cells, reporter gene expression provided specific information on the number of surviving cells. This multimodality approach allows complementary analysis of cell localization and viability.