Abstract
We tested the hypothesis that allogenic adipose-derived mesenchymal stem cells (ADMSCs) alleviated brain death (BD)-induced remote organ damage and events of post heart-transplant acute rejection. To determine the impact of BD on remote organ damage, adult-male F344 rats (n=24) were categorized sham-control (SC), BD and BDMSC (allogenic ADMSC/1.2 × 106 cells/derived from F344 by intravenous transfusion 3 h after BD procedure). To determine the protective effect of allogenic ADMSCs, animals (n=8/each group in F344/Lewis) were categorized into groups BD-T(F344 heart transplanted into Lewis by 6h after BD), BD-TMSC(D1/3) (BD induction for 6h then heart transplantation, and allogenic ADMSCs transfusion at days 1 and 5 after heart transplantation), BD-TMSC(3h) (BD + ADMSC/1.2 × 106 cells at 3h and heart transplantation at 6h after BD) and BD-TMSC(3h, D1/3) [BD + ADMSC/1.2 × 106 cells at 3h and heart transplantation at 6h after BD, then ADMSC therapy by days 1/3]. At day 5 post procedure, liver, kidney and heart specimens showed higher molecular-cellular levels of inflammation, immune reaction, apoptosis and fibrosis in BD than in SC that were reversed in BDMSC (all P < 0.0001). These molecular-cellular expressions and circulating/splenic levels of innate/adoptive immune cells were higher in BD-T, lowest in BD-TMSC(3h, D1/3) and higher BD-TMSC(3h) in than BD-TMSC(D1/3), whereas heart function showed an opposite pattern among the four groups (all P < 0.001). In conclusion, ADMSCs suppressed BD-caused remote organ damage and heart-transplant rejection.
Highlights
Advanced congestive heart failure (CHF) in its terminal stage is the most important contributor to cardiac death among all cardiovascular diseases [1,2,3]
The results showed that during the brain death (BD) period, the mean heart rate was about 255.98 beats/min and the mean blood pressure was 42.6 mmHg, suggesting www.impactjournals.com/oncotarget the experimental model of BD was successfully created
To elucidate the circulating level of inflammatory reaction after BD, the enzyme-linked immunosorbent assay (ELISA) and flow cytometric analysis were utilized in the present study
Summary
Advanced congestive heart failure (CHF) in its terminal stage is the most important contributor to cardiac death among all cardiovascular diseases [1,2,3]. For the second issue, pre-transplant major histocompatibility complex (MHC) matching between donor and recipient has been routine and advanced immunosuppressive regimens have been extensively utilized after heart transplantation, rejection is still a bottleneck for transplant success. This suggests that unidentified confounders may exist. Experimental studies have demonstrated that vigorous inflammatory reaction and hyper-reactive immune response commonly occur in circulation [37] and in major organs such as liver, heart and kidney after BD in animals [34,35,36]. Using an experimental model of BD and heart transplantation, we tested the hypothesis that ADMSC therapy might effectively protect remote organs from BD-induced injury and acute rejection after heart transplantation in rodents
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