Adult Bone Marrow-Derived Mesenchymal Stem Cells Seeded on Tissue-Engineered Cardiac Patch Contribute to Myocardial Scar Remodeling and Enhance Revascularization in a Rabbit Model of Chronic Myocardial Infarction
DOI:
https://doi.org/10.1532/hsf.5067Keywords:
myocardial infarction, bone marrow-derived mesenchymal stem cells, tissue engineering, remodeling, revascularizationAbstract
Background: Although the transplantation of tissue-engineered cardiac patches with adult bone marrow-derived mesenchymal stem cells (MSCs) can enhance cardiac function after acute or chronic myocardial infarction (MI), the recovery mechanism remains controversial. This experiment aimed to investigate the outcome measurements of MSCs within a tissue-engineered cardiac patch in a rabbit chronic MI model.
Methods: This experiment was divided into four groups: left anterior descending artery (LAD) sham-operation group (N = 7), sham-transplantation (control, N = 7), non-seeded patch group (N = 7), and MSCs-seeded patch group (N = 6). PKH26 and 5-Bromo-2’-deoxyuridine (BrdU) labeled MSCs-seeded or non-seeded patches were transplanted onto chronically infarct rabbit hearts. Cardiac function was evaluated by cardiac hemodynamics. H&E staining was performed to count the number of vessels in the infarcted area. Masson staining was used to observe cardiac fiber formation and to measure scar thickness.
Results: Four weeks after transplantation, a remarkable improvement in cardiac functionality could be distinctly observed, which was most significant in the MSCs-seeded patch group. Moreover, labeled cells were detected in the myocardial scar, with most of them differentiated into myofibroblasts, some into smooth muscle cells, and only a few into cardiomyocytes in the MSCs-seeded patch group. We also observed significant revascularization in the infarct area implanted in either MSCs-seeded or non-seeded patches. In addition, there were significantly greater numbers of microvessels in the MSCs-seeded patch group than in the non-seeded patch group.
References
Alfaro MP, Pagni M, Vincent A, et al. 2008. The Wnt modulator sFRP2 enhances mesenchymal stem cell engraftment, granulation tissue formation and myocardial repair. Proc Natl Acad Sci U S A. 105(47):18366-18371.
Badylak SF, Lantz GC, Coffey A, Geddes LA. 1989. Small intestinal submucosa as a large diameter vascular graft in the dog. J Surg Res. 47(1):74-80.
Chacko SM, Khan M, Kuppusamy ML, et al. 2009. Myocardial oxygenation and functional recovery in infarct rat hearts transplanted with mesenchymal stem cells. Am J Physiol Heart Circ Physiol. 296(5):H1263-1273.
Chang Y, Lai PH, Wei HJ, et al. 2007. Tissue regeneration observed in a basic fibroblast growth factor-loaded porous acellular bovine pericardium populated with mesenchymal stem cells. J Thorac Cardiovasc Surg. 134(1):65-73, 73 e61-64.
Chen CH, Wei HJ, Lin WW, et al. 2008. Porous tissue grafts sandwiched with multilayered mesenchymal stromal cell sheets induce tissue regeneration for cardiac repair. Cardiovasc Res. 80(1):88-95.
Chen SL, Fang WW, Ye F, et al. 2004. Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. Am J Cardiol. 94(1):92-95.
Davani S, Marandin A, Mersin N, et al. 2003. Mesenchymal progenitor cells differentiate into an endothelial phenotype, enhance vascular density, and improve heart function in a rat cellular cardiomyoplasty model. Circulation. 108 Suppl 1(II253-258.
Derval N, Barandon L, Dufourcq P, et al. 2008. Epicardial deposition of endothelial progenitor and mesenchymal stem cells in a coated muscle patch after myocardial infarction in a murine model. Eur J Cardiothorac Surg. 34(2):248-254.
Frangogiannis NG, Shimoni S, Chang SM, et al. 2002. Active interstitial remodeling: an important process in the hibernating human myocardium. J Am Coll Cardiol. 39(9):1468-1474.
Fujita M, Morimoto Y, Ishihara M, et al. 2004. A new rabbit model of myocardial infarction without endotracheal intubation. J Surg Res. 116(1):124-128.
Hattan N, Kawaguchi H, Ando K, et al. 2005. Purified cardiomyocytes from bone marrow mesenchymal stem cells produce stable intracardiac grafts in mice. Cardiovasc Res. 65(2):334-344.
Jones E, McGonagle D. 2008. Human bone marrow mesenchymal stem cells in vivo. Rheumatology (Oxford). 47(2):126-131.
Kamihata H, Matsubara H, Nishiue T, et al. 2001. Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines. Circulation. 104(9):1046-1052.
Kinnaird T, Stabile E, Burnett MS, et al. 2004. Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation. 109(12):1543-1549.
Kinnaird T, Stabile E, Burnett MS, et al. 2004. Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ Res. 94(5):678-685.
Kocher AA, Schuster MD, Szabolcs MJ, et al. 2001. Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med. 7(4):430-436.
Krupnick AS, Kreisel D, Engels FH, et al. 2002. A novel small animal model of left ventricular tissue engineering. J Heart Lung Transplant. 21(2):233-243.
Le Blanc K. 2003. Immunomodulatory effects of fetal and adult mesenchymal stem cells. Cytotherapy. 5(6):485-489.
Liao B, Deng L, & Wang F. 2006. [Effects of bone marrow mesenchymal stem cells enriched by small intestinal submucosal films on cardiac function and compensatory circulation after myocardial infarction in goats]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 20(12):1248-1252.
Mangi AA, Noiseux N, Kong D, et al. 2003. Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts. Nat Med. 9(9):1195-1201.
Messina LM, Podrazik RM, Whitehill TA, et al. 1992. Adhesion and incorporation of lacZ-transduced endothelial cells into the intact capillary wall in the rat. Proc Natl Acad Sci USA. 89(24):12018-12022.
Miyagawa S, Sawa Y, Taketani S, et al. 2002. Myocardial regeneration therapy for heart failure: hepatocyte growth factor enhances the effect of cellular cardiomyoplasty. Circulation. 105(21):2556-2561.
Mollmann H, Nef HM, Kostin S, et al. 2006. Bone marrow-derived cells contribute to infarct remodelling. Cardiovasc Res. 71(4):661-671.
Nagaya N, Kangawa K, Itoh T, et al. 2005. Transplantation of mesenchymal stem cells improves cardiac function in a rat model of dilated cardiomyopathy. Circulation. 112(8):1128-1135.
Ng F, Boucher S, Koh S, et al. 2008. PDGF, TGF-beta, and FGF signaling is important for differentiation and growth of mesenchymal stem cells (MSCs): transcriptional profiling can identify markers and signaling pathways important in differentiation of MSCs into adipogenic, chondrogenic, and osteogenic lineages. Blood. 112(2):295-307.
Piao H, Youn TJ, Kwon JS, et al. 2005. Effects of bone marrow derived mesenchymal stem cells transplantation in acutely infarcting myocardium. Eur J Heart Fail. 7(5):730-738.
Pittenger MF, Mackay AM, Beck SC, et al. 1999. Multilineage potential of adult human mesenchymal stem cells. Science. 284(5411):143-147.
Potapova IA, Doronin SV, Kelly DJ, et al. 2008. Enhanced recovery of mechanical function in the canine heart by seeding an extracellular matrix patch with mesenchymal stem cells committed to a cardiac lineage. Am J Physiol Heart Circ Physiol. 295(6):H2257-2263.
Prockop DJ. 1997. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science. 276(5309):71-74.
Raff M. 2003. Adult stem cell plasticity: fact or artifact? Annu Rev Cell Dev Biol. 19(1-22).
Shake JG, Gruber PJ, Baumgartner WA, et al. 2002. Mesenchymal stem cell implantation in a swine myocardial infarct model: engraftment and functional effects. Ann Thorac Surg. 73(6):1919-1925; discussion 1926.
Sun Y, Weber KT. 1996. Angiotensin converting enzyme and myofibroblasts during tissue repair in the rat heart. J Mol Cell Cardiol. 28(5):851-858.
Takemura G, Ohno M, Hayakawa Y, et al. 1998. Role of apoptosis in the disappearance of infiltrated and proliferated interstitial cells after myocardial infarction. Circ Res. 82(11):1130-1138.
Tan MY, Zhi W, Wei RQ, et al. 2009. Repair of infarcted myocardium using mesenchymal stem cell seeded small intestinal submucosa in rabbits. Biomaterials. 30(19):3234-3240.
Toma C, Pittenger MF, Cahill KS, Byrne BJ, Kessler PD. 2002. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation. 105(1):93-98.
Tomita S, Li RK, Weisel RD, et al. 1999. Autologous transplantation of bone marrow cells improves damaged heart function. Circulation. 100(19 Suppl):II247-256.
Wagers AJ, Weissman IL. 2004. Plasticity of adult stem cells. Cell. 116(5):639-648.
Weber KT, Sun Y, Katwa LC, Cleutjens JP. 1995. Connective tissue: a metabolic entity? J Mol Cell Cardiol. 27(1):107-120.
