Background
Ischemia/reperfusion (I/R) injury is an inevitable consequence of organ transplantation
and a major determinant of patient and graft survival in heart transplantation. Bone
marrow–mesenchymal stromal cell (BM-MSC) treatment is a potentially effective cell
therapy for cardiac disease. We investigated the effects of intravenous delivery of
BM-MSCs in the acute phase post-transplant in a heterotopic heart transplantation
(HHT) model associated with I/R injury.
Methods
Hearts of wild-type Lewis (WT LEW) rats were harvested and transplanted heterotopically
into the necks of recipient WT LEW rats. Forty-eight hours after HHT, BM-MSCs were
injected intravenously into animals in the experimental group, whereas controls received
normal saline (NS).
Results
Eight days after BM-MSC injection, fractional shortening of transplanted hearts was
significantly higher and left ventricular systolic diameter was lower in the BM-MSC
group compared with controls, whereas no differences were found 28 days after infusion.
A reduction in ventricular remodeling and cardiac fibrosis was observed by histochemical
analysis and confirmed by cardiac magnetic resonance imaging in the BM-MSC group.
The perivascular stromal cells’ density and the number of capillaries were increased
whereas the number of apoptotic cells decreased significantly in transplanted hearts
in the BM-MSC group compared with the NS group.
Conclusions
We showed early improvement in cardiac function and subsequent enhanced ventricular
remodeling, reduced cardiac fibrosis, augmented neo-vascularization and decreased
cardiomyocyte apoptosis of the transplanted heart in a heterotopic transplantation
model after intravenous infusion of BM-derived MSCs. Our data suggest that clinical
studies with BM-MSCs are warranted to understand their effects on cardiac graft and
transplant recipient survival.
KEYWORDS
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References
- Heart transplantation in adults with end-stage congenital heart disease.Future Cardiol. 2012; 8: 329-342
- The registry of the International Society for Heart and Lung Transplantation: 29th adult lung and heart–lung transplant report—2012.J Heart Lung Transplant. 2012; 31: 1073-1086
- Heart transplantation.Crit Care Nursing Clin N Am. 2011; 23: 471-479
- Primary graft failure after heart transplantation: urgent need for a consensus guideline.Transplantation. 2011; 91: e31
- Myocardial ischemia reperfusion injury: from basic science to clinical bedside.Sem Cardiothorac Vasc Anesth. 2012; 16: 123-132
- Ischemia/reperfusion injury protection by mesenchymal stem cell derived antioxidant capacity.Stem Cells Dev. 2013; 22: 2497-2507
- Ischemia-reperfusion injury: beneficial effects of mesenchymal stromal cells.Curr Opin Organ Transplant. 2013; 18: 34-43
- Localization of mesenchymal stromal cells dictates their immune or proinflammatory effects in kidney transplantation.Am J Transplant. 2012; 12: 2373-2383
- Nitric oxide augments mesenchymal stem cell ability to repair liver fibrosis.J Transl Med. 2012; 10: 75
- Ischemia postconditioning and mesenchymal stem cells engraftment synergistically attenuate ischemia reperfusion-induced lung injury in rats.J Surg Res. 2012; 178: 81-91
- Mesenchymal stem cells: application for solid-organ transplantation.Curr Opin Organ Transplant. 2012; 17: 55-62
- Historical perspective on the pathology of myocardial ischemia/reperfusion injury.Circ Res. 2013; 113: 428-438
- To H, et al. Simplified method of heterotopic rat heart transplantation using the cuff technique: application to sublethal dose protocol of methotrexate on allograft survival.Microsurgery. 2001; 21: 16-21
- A technique for accessory cervical heart transplantation in rabbits and rats.Acta Pathol Microbiol Scand A Pathol. 1971; 79: 366-372
- Non-suture organ grafting to the neck vessels in rats.Acta Chir Scand. 1984; 150: 463-467
- Bone marrow-derived mesenchymal stromal cells express cardiac-specific markers, retain the stromal phenotype, and do not become functional cardiomyocytes in vitro.Stem Cells. 2008; 26: 2884-2892
- Green fluorescent protein-transgenic rat: a tool for organ transplantation research.Biochem Biophys Res Commun. 2001; 286: 779-785
- Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement.Cytotherapy. 2006; 8: 315-317
- Pathogenesis of myocardial ischemia-reperfusion injury and rationale for therapy.Am J Cardiol. 2010; 106: 360-368
- Complement-mediated ischemia-reperfusion injury: lessons learned from animal and clinical studies.Ann Surg. 2009; 249: 889-899
- Mesenchymal stem cells transmigrate between and directly through tumor necrosis factor-alpha-activated endothelial cells via both leukocyte-like and novel mechanisms.Stem Cells. 2012; 30: 2472-2486
- Mechanisms of immune modulation by mesenchymal stromal cells and clinical translation.Curr Mol Med. 2013; 13: 856-867
- Myocardial ischemia-reperfusion injury: a neglected therapeutic target.J Clin Iinvest. 2013; 123: 92-100
- Extracellular vesicles released from mesenchymal stromal cells modulate miRNA in renal tubular cells and inhibit ATP depletion injury.Stem cells and development. 2014; 23: 1809-1819
- Therapeutic use of stem cell transplantation for cell replacement or cytoprotective effect of microvesicle released from mesenchymal stem cell.Mol Cells. 2014; 37: 133-139
- Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury..Stem Cell Res. 2014; 4: 214-222
- Remote transplantation of mesenchymal stem cells protects the heart against ischemia-reperfusion injury.Stem Cells. 2014; 32: 2123-2134
- Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion.Front Immunol. 2012; 3: 297
- Bone-derived stem cells repair the heart after myocardial infarction through transdifferentiation and paracrine signaling mechanisms.Circ Res. 2013; 113: 539-552
- Proinflammatory cytokine effects on mesenchymal stem cell therapy for the ischemic heart.Ann Thorac Surg. 2009; 88: 1036-1043
- Mesenchymal stromal cells mediate a switch to alternatively activated monocytes/macrophages after acute myocardial infarction.Basic Res Cardiol. 2011; 106: 1299-1310
- Mesenchymal stem cell therapy for cardiac inflammation: immunomodulatory properties and the influence of toll-like receptors.Mediat Inflamm. 2013; (2013): 181020
- Successful transplantation of rat hearts subjected to extended cold preservation with a novel preservation solution.Transplant Int. 2012; 25: 696-706
- Dynamic patterns of ventricular remodeling and apoptosis in hearts unloaded by heterotopic transplantation.J Heart Lung Transplant. 2014; 33: 203-210
- Contractile function is preserved in unloaded hearts despite atrophic remodeling.J Thorac Cardiovasc Surg. 2009; 137: 742-746
- Effects of ventricular unloading on apoptosis and atrophy of cardiac myocytes.J Surg Res. 2004; 120: 119-126
- Mesenchymal stromal (stem) cells to improve solid organ transplant outcome: lessons from the initial clinical trials.Curr Opin Organ Transplant. 2013; 18: 672-681
Article info
Publication history
Published online: June 11, 2015
Identification
Copyright
© 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.
