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Brain-dead donor heart conservation with a preservation solution supplemented by a conditioned medium from
Sevil Korkmaz-Icöz1, Kunsheng Li1, Sivakkanan Loganathan1,2,3
1Department of Cardiac Surgery, Heidelberg University Hospital, Heidelberg, Germany.
Insights
Mesenchymal stem cell conditioned medium (CM) improves heart graft function after brain death (BD) by preserving systolic function and reducing apoptosis. The PI3K/Akt pathway is not the primary mechanism behind these protective effects.
Area of Science:
- Cardiology
- Regenerative Medicine
- Transplantation Immunology
Background:
- Brain death (BD) in organ donors can lead to hemodynamic instability and post-transplant graft dysfunction.
- Mesenchymal stem cells (MSCs) and their conditioned medium (CM) show potential in protecting organs during transplantation.
- The PI3K/Akt pathway is a known signaling pathway involved in cell survival and function.
Purpose of the Study:
- To investigate the efficacy of MSC-derived CM in preserving heart graft function from BD donors.
- To explore the role of the PI3K pathway in the protective effects of CM on cardiac grafts.
Main Methods:
- Donor rats were subjected to either sham operation or BD induction.
- Hearts were preserved in cardioplegic solution with either vehicle, MSC-CM, or a PI3K inhibitor (LY294002).
- Graft function was assessed post-transplantation, along with apoptosis markers (TUNEL, endonuclease G).
Main Results:
- BD significantly reduced cardiac systolic performance and increased apoptosis compared to sham.
- Preservation with MSC-CM improved systolic graft function and reduced apoptosis in BD hearts.
- Inhibition of the PI3K pathway partially abrogated the protective benefits of CM.
Conclusions:
- MSC-derived CM effectively improves cardiac allograft function and reduces apoptosis in the context of brain death.
- The PI3K/Akt pathway is not the primary mediator of CM's protective effects on cardiac contractility and caspase-independent apoptosis.
Abstract:
Hearts are usually procured from brain-dead (BD) donors. However, brain death may induce hemodynamic instability, which may contribute to posttransplant graft dysfunction. We hypothesized that BD-donor heart preservation with a conditioned medium (CM) from mesenchymal stem cells (MSCs) would improve graft function after transplantation. Additionally, we explored the PI3K pathway's potential role. Rat MSCs-derived CM was used for conservation purposes. Donor rats were either exposed to sham operation or brain death by inflation of a subdural balloon-catheter for 5.5 hours. Then, the hearts were explanted, stored in cardioplegic solution-supplemented with either a medium vehicle (BD and sham), CM (BD + CM), or LY294002, an inhibitor of PI3K (BD + CM + LY), and finally transplanted. Systolic performance and relaxation parameters were significantly reduced in BD-donors compared to sham. After transplantation, systolic and diastolic functions were significantly decreased, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive cells and endonuclease G positive cells were increased in the BD-group compared to sham. Preservation of BD-donor hearts with CM resulted in a recovery of systolic graft function (dP/dtmax : BD + CM: 3148 ± 178 vs BD: 2192 ± 94 mm Hg/s at 110 µL, P < .05) and reduced apoptosis. LY294002 partially lowered graft protection afforded by CM in the BD group. Our data suggest that PI3K/Akt pathway is not the primary mechanism of action of CM in improving posttransplant cardiac contractility and preventing caspase-independent apoptosis.
