Pulmonary Passage is a Major Obstacle for Intravenous Stem Cell Delivery: The Pulmonary First-Pass Effect
Pulmonary Passage is a Major Obstacle for Intravenous Stem Cell Delivery: The Pulmonary First-Pass Effect
复制标题
DOI：
10.1089/scd.2008.0253
复制
发表时间：
2009-06-01
影响因子：
4
通讯作者：
Cox, Charles S., Jr.
中科院分区：
文献类型：
--
作者：
Fischer, Uwe M.;Harting, Matthew T.;Cox, Charles S., Jr.
静脉注射（IV）干细胞用于再生组织治疗已越来越多地用于实验和临床试验。然而，最近的数据表明，大多数给药的干细胞最初被困在肺部。我们试图研究可能影响这种肺部首过效应的变量。麻醉后的Sprague-Dawley大鼠，在左颈内静脉和颈总动脉内置入硅胶管导管。我们研究了四种不同的细胞类型：间充质基质细胞（MSC）、多能成体祖细胞（MAPCs）、骨髓源性单个核细胞（BMMC）和神经干细胞（NSC）。用Qtracker (R) 655（用于流式细胞术）和Qtracker (R) 800（用于红外成像）对细胞进行共标记，并通过静脉注射持续收集动脉样本。通过流式细胞术分析样品，检测到达动脉循环的标记细胞。在取样和放血后，心脏、肺、脾、肾和肝被采集并放置在红外成像系统上以识别标记细胞的存在。静脉输注后，大多数间充质干细胞被困在肺内。与MSCs相比，NSC和MAPC肺通道增加2倍，BMMC肺通道增加30倍。抑制MSC CD49d显著增加MSC肺通道。与单次给药相比，两次给药增加了肺间充质干细胞的传代。红外成像显示干细胞均匀分布在所有肺野。静脉给药后，较大的干细胞和祖细胞最初被困在肺内，而到达动脉系统的细胞数量在治疗上存在问题。
Intravenous (IV)stem cell delivery for regenerative tissue therapy has been increasingly used in both experimental and clinical trials. However, recent data suggest that the majority of administered stem cells are initially trapped in the lungs. We sought to investigate variables that may affect this pulmonary first-pass effect. In anesthetized Sprague-Dawley rats, silicone tubing catheters were placed in the left internal jugular vein and common carotid artery. We investigated four different cell types: mesenchymal stromal cells (MSC), multipotent adult progenitor cells (MAPCs), bone marrow-derived mononuclear cells (BMMC), and neural stem cells (NSC). Cells were co-labeled with Qtracker (R) 655 ( for flow cytometry) and Qtracker (R) 800 ( for infrared imaging) and infused intravenously with continual arterial sample collection. Samples were analyzed via flow cytometry to detect labeled cells reaching the arterial circulation. Following sampling and exsanguination, heart, lungs, spleen, kidney, and liver were harvested and placed on an infrared imaging system to identify the presence of labeled cells. The majority of MSCs were trapped inside the lungs following intravenous infusion. NSC and MAPC pulmonary passage was 2-fold and BMMC passage was 30-fold increased as compared to MSCs. Inhibition of MSC CD49d significantly increased MSC pulmonary passage. Infusion via two boluses increased pulmonary MSC passage as compared to single bolus administration. Infrared imaging revealed stem cells evenly distributed over all lung fields. Larger stem and progenitor cells are initially trapped inside the lungs following intravenous administration with a therapeutically questionable number of cells reaching the arterial system acutely.