title: Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect.
abstract: 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 655 (for flow cytometry) and Qtracker 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.
authors.affiliation: Department of Pediatric Surgery, University of Texas Medical School at Houston, 6431 Fannin Street, Houston, TX 77030, USA.
authors.forename: Uwe M
authors.initials: UM
authors.lastname: Fischer
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Harting
authors.forename: Fernando
authors.initials: F
authors.lastname: Jimenez
authors.forename: Werner O
authors.initials: WO
authors.lastname: Monzon-Posadas
authors.forename: Hasen
authors.initials: H
authors.lastname: Xue
authors.forename: Sean I
authors.initials: SI
authors.lastname: Savitz
authors.forename: Glen A
authors.initials: GA
authors.lastname: Laine
authors.forename: Charles S
authors.initials: CS
authors.lastname: Cox
mesh_terms: D000818:Animals; D001158:Arteries / Q000166:cytology; D048429:Cell Size; D005434:Flow Cytometry; D007259:Infrared Rays; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008168:Lung / Q000166:cytology*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D009928:Organ Specificity; D051381:Rats; D017207:Rats, Sprague-Dawley