Impact of Escaped Bone Marrow Mesenchymal Stromal Cells on Extracardiac Organs after Intramyocardial Implantation in a Rat Myocardial Infarction Model

Abstract

Cell escape occurs after intramyocardial injection for treatment of myocardial infarction (MI) and then the migrated cells might be entrapped by extracardiac organs. We investigated the fate of migrated bone marrowderived mesenchymal stromal cells (MSCs) and their impact on lung, liver, and spleen. MI model was created by coronary artery ligation in female Lewis rats. Three weeks after the ligation, bromodeoxyuridine (BrdU)-labeled male MSCs were directly injected into the infarcted area in the cell transplantation group (n = 22). The same volume of phosphate-buffered solution (PBS) was injected in the control group (n = 21). In the sham group (n = 10) intramyocardial injection of the same volume of PBS was performed in healthy rats. Four weeks later, echocardiography was performed and the cell retention was evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemistry study was performed to identify the migrated cells. Heart function was improved after the cell injection. qRT-PCR results showed the percentage of retained cells in heart, spleen, liver, and lung ranked 3.63 ± 0.48%, 0.77 ± 0.13%, 0.68 ± 0.10%, 0.62 ± 0.11%, respectively, after cell transplantation. The implanted MSCs that escaped to liver, spleen, and lung did not differentiate into fibroblast, myofibroblast, or alveolar epithelial cells. However, the migrated MSCs in liver expressed functional hepatocyte marker. In conclusion, cell migration after intramyocardial injection did not result in deterioration of lung, liver, and spleen function. Our study might pave the way for new safety investigation of emerging cell resources and their impact on target and untargeted organs.Key words: Bone marrow mesenchymal stromal cells; Myocardial infarction; Lung; Liver; Spleen INTRODUCTIONfilter organs in pulmonary or systemic circulation (7,9, 27). Until now, little is known about the impact of escaped progenitor cells on extracardiac organs. ThereBone marrow-derived mesenchymal stromal cells (MSCs), which contain multipotent mesenchymal stem fore, in the present study we address 1) the cell retention after intramyocardial injection in a chronic MI model cells, have been a popular cell resource for cardiac regeneration in recent years (18). The therapeutic potency and 2) the fate and impact of escaped MSCs on liver, spleen, and lung. of MSC transplantation for the treatment of myocardial infarction (MI) has been well demonstrated in experi-MATERIALS AND METHODS mental and clinical studies. Intramyocardial injection is Animals considered as the most effective route for the precise cell delivery to the target areas. However, many cells Seventy syngenic Lewis rats (Vital River Laboratory Animal, Inc., Beijing, China) weighing 200-250 g were still migrated from the injection sites to the extracardiac organs, and these cells tended to be entrapped by the enrolled in this study. All animals received humane careReceived rats were sacrificed and the lung tissue homogenized. Cell CultureTumor necrosis factor-α (TNF-α) and interleukin-...

Remote Ischemic Postconditioning Ameliorates the Mesenchymal Stem Cells Engraftment in Reperfused Myocardium

“…However, low cell engraftment and survival in myocardial milieu are still the main restraints in current experimental and clinical studies with all the available cells therapy [ 8 ].Although intramyocaridal MSCs transplantation is most efficacious compared with other delivery routes, the retention is still less than optimal [ 16 ]. Apart from cell evasion from the injected site [ 17 , 18 ], the hostile milieu in ischemic myocardium which ischaracteristic of ischemia, inflammation and oxidative stress was mainly accountable for severe loss. All kinds of methods have been resorted to enhance the therapeutics benefit, including cell pretreatment with hypoxia[ 19 ], tissue engineering and genetic manipulation.…”

Central zone of myocardial infarction: a neglected target area for heart cell therapy

“…As showed in Figure 8, the thickness of the CZ of MI was less than 1 mm, and therefore was very easy to penetrate the scar into the ventricular cavity during cell injection. A failed injection would cause bleeding from the injection site, and could also cause the cells to be washed from the left side of the heart cavity and pumped into the systemic circulation, which may cause safety issues [14, 15]. However, in this study, during the procedure of cell delivery, we did not observe any bleeding in the CZC group.…”

Cardiac cell therapy: current status and future trends

“…In one experiment, MSCs were distributed to a wide range of tissues including gastrointestinal tissues, lung, skin, thymus, etc. after intravenous infusion (Devine et al , 2003;Wang et al ., 2010). Our previous study also revealed extensive extracardiac cell distribution after intramyocardial injection into the border zone of an acute MI area (Zhang et al ., 2007;Wang et al , 2010) (Fig.…”