An emerging concept is that the mammalian myocardium has the potential to regenerate, but that regeneration might be too inefficient to repair the extensive myocardial injury that is typical of human disease [1][2][3][4][5][6][7][8] . However, the degree to which stem cells or precursor cells contribute to the renewal of adult mammalian cardiomyocytes remains controversial. Here we report evidence that stem cells or precursor cells contribute to the replacement of adult mammalian cardiomyocytes after injury but do not contribute significantly to cardiomyocyte renewal during normal aging. We generated doubletransgenic mice to track the fate of adult cardiomyocytes in a 'pulse-chase' fashion: after a 4-OHtamoxifen pulse, green fluorescent protein (GFP) expression was induced only in cardiomyocytes, with 82.7% of cardiomyocytes expressing GFP. During normal aging up to one year, the percentage of GFP + cardiomyocytes remained unchanged, indicating that stem or precursor cells did not refresh uninjured cardiomyocytes at a significant rate during this period of time. By contrast, after myocardial infarction or pressure overload, the percentage of GFP + cardiomyocytes decreased from 82.8% in heart tissue from sham-treated mice to 67.5% in areas bordering a myocardial infarction, 76.6% in areas away from a myocardial infarction, and 75.7% in hearts subjected to pressure overload, indicating that stem cells or precursor cells had refreshed the cardiomyocytes.Despite recent enthusiasm about the idea of regenerating myocardium by using resident cardiac stem cells, fundamental questions remain unanswered. Are cardiomyocytes constantly replaced by endogenous stem or precursor cells? Does injury lead to replacement with new cardiomyocytes from a stem cell pool? It is essential to answer these questions unambiguously and quantitatively.
Strategies for cardiac repair include injection of cells, but these approaches have been hampered by poor cell engraftment, survival, and differentiation. To address these shortcomings for the purpose of improving cardiac function after injury, we designed self-assembling peptide nanofibers for prolonged delivery of insulin-like growth factor 1 (IGF-1), a cardiomyocyte growth and differentiation factor, to the myocardium, using a ''biotin sandwich'' approach. Biotinylated IGF-1 was complexed with tetravalent streptavidin and then bound to biotinylated self-assembling peptides. This biotin sandwich strategy allowed binding of IGF-1 but did not prevent self-assembly of the peptides into nanofibers within the myocardium. IGF-1 that was bound to peptide nanofibers activated Akt, decreased activation of caspase-3, and increased expression of cardiac troponin I in cardiomyocytes. After injection into rat myocardium, biotinylated nanofibers provided sustained IGF-1 delivery for 28 days, and targeted delivery of IGF-1 in vivo increased activation of Akt in the myocardium. When combined with transplanted cardiomyocytes, IGF-1 delivery by biotinylated nanofibers decreased caspase-3 cleavage by 28% and increased the myocyte cross-sectional area by 25% compared with cells embedded within nanofibers alone or with untethered IGF-1. Finally, cell therapy with IGF-1 delivery by biotinylated nanofibers improved systolic function after experimental myocardial infarction, demonstrating how engineering the local cellular microenvironment can improve cell therapy.engineering ͉ maturation ͉ scaffold
Mammalian cardiomyocytes have limited proliferation potential, and acutely injured mammalian hearts do not regenerate adequately. Instead, injured myocardium develops fibrosis and scarring. Here we show that FGF1͞p38 MAP kinase inhibitor treatment after acute myocardial injury in 8-to 10-week-old rats increases cardiomyocyte mitosis. At 3 months after injury, 4 weeks of FGF1͞p38 MAP kinase inhibitor therapy results in reduced scarring and wall thinning, with markedly improved cardiac function. In contrast, p38 MAP kinase inhibition alone fails to rescue heart function despite increased cardiomyocyte mitosis. FGF1 improves angiogenesis, possibly contributing to the survival of newly generated cardiomyocytes. Our data indicate that FGF1 and p38 MAP kinase, proteins involved in cardiomyocyte proliferation and angiogenesis during development, may be delivered therapeutically to enhance cardiac regeneration.cardiac regeneration ͉ fractional shortening ͉ Cyclin D2 ͉ Cyclin A ͉ angiogenesis
Endothelial cells can protect cardiomyocytes from injury, but the mechanism of this protection is incompletely described. Here we demonstrate that protection of cardiomyocytes by endothelial cells occurs through PDGF-BB signaling. PDGF-BB induced cardiomyocyte Akt phosphorylation in a time-and dose-dependent manner and prevented apoptosis via PI3K/Akt signaling. Using injectable self-assembling peptide nanofibers, which bound PDGF-BB in vitro, sustained delivery of PDGF-BB to the myocardium at the injected sites for 14 days was achieved. A blinded and randomized study in 96 rats showed that injecting nanofibers with PDGF-BB, but not nanofibers or PDGF-BB alone, decreased cardiomyocyte death and preserved systolic function after myocardial infarction. A separate blinded and randomized study in 52 rats showed that PDGF-BB delivered with nanofibers decreased infarct size after ischemia/reperfusion. PDGF-BB with nanofibers induced PDGFR-β and Akt phosphorylation in cardiomyocytes in vivo. These data demonstrate that endothelial cells protect cardiomyocytes via PDGF-BB signaling and that this in vitro finding can be translated into an effective in vivo method of protecting myocardium after infarction. Furthermore, this study shows that injectable nanofibers allow precise and sustained delivery of proteins to the myocardium with potential therapeutic benefits.
Communication between endothelial cells and cardiomyocytes regulates not only early cardiac development but also adult cardiomyocyte function, including the contractile state. In the normal mammalian myocardium, each cardiomyocyte is surrounded by an intricate network of capillaries and is next to endothelial cells. Cardiomyocytes depend on endothelial cells not only for oxygenated blood supply but also for local protective signals that promote cardiomyocyte organization and survival. While endothelial cells direct cardiomyocytes, cardiomyocytes reciprocally secrete factors that impact endothelial cell function. Understanding how endothelial cells communicate with cardiomyocytes will be critical for cardiac regeneration, in which the ultimate goal is not simply to improve systolic function transiently but to establish new myocardium that is both structurally and functionally normal in the long term.
Background-Growing evidence suggests that intramyocardial biomaterial injection improves cardiac functions after myocardial infarction (MI) in rodents. Cell therapy is another promising approach to treat MI, although poor retention of transplanted cells is a major challenge. In this study, we hypothesized that intramyocardial injection of self-assembling peptide nanofibers (NFs) thickens the infarcted myocardium and increases transplanted autologous bone marrow mononuclear cell (MNC) retention to attenuate cardiac remodeling and dysfunction in a pig MI model. Methods and Results-A total of 40 mature minipigs were divided into 5 groups: sham, MIϩnormal saline, MIϩNFs, MIϩMNCs, and MIϩMNCs/NFs. MI was induced by coronary occlusion followed by intramyocardial injection of 2 mL normal saline or 1% NFs with or without 1ϫ10 8 isolated autologous MNCs. NF injection significantly improved diastolic function and reduced ventricular remodeling 28 days after treatment. Injection of MNCs alone ameliorated systolic function only, whereas injection of MNCs with NFs significantly improved both systolic and diastolic functions as indicated by ϩdP/dt and ϪdP/dt (1214.5Ϯ91.9 and Ϫ1109.7Ϯ91.2 mm Hg/s in MIϩNS, 1693.7Ϯ84.7 and Ϫ1809.6Ϯ264.3 mm Hg/s in MIϩMNCs/NFs, respectively), increased transplanted cell retention (29.3Ϯ4.5 cells/mm 2 in MIϩMNCs and 229.4Ϯ41.4 cells/mm 2 in MIϩMNCs/NFs) and promoted capillary density in the peri-infarct area. Conclusions-We demonstrated that NF injection alone prevents ventricular remodeling, whereas cell implantation withNFs improves cell retention and cardiac functions after MI in pigs. This unprecedented combined treatment in a large animal model has therapeutic effects, which can be translated to clinical applications in the foreseeable future. (Circulation. 2010; 122[suppl 1]:S132-S141.)Key Words: biomaterials Ⅲ bone marrow mononuclear cells Ⅲ cardiac tissue engineering Ⅲ myocardial infarction C ongestive heart failure is a leading cause of death in the United States and other developed countries. The dominant cause of heart failure is loss of myocardium due to coronary artery disease and the limited regeneration potential of cardiomyocytes. Cardiac tissue engineering is a promising and actively developing area of research aiming to repair, replace, and regenerate the myocardium. Several studies have demonstrated the feasibility of this approach and indicated that direct injection of biomaterials into the infarcted myocardium may be beneficial in preventing deleterious remodeling and reducing cardiac dysfunction. [1][2][3][4] Previous studies using intramyocardial injection of self-assembling peptide nanofibers (NFs), a highly biocompatible 5,6 and biodegradable 7 material, have also revealed their therapeutic potentials for angiogenesis, controlled drug/growth factor release, cell delivery, and stem cell recruitment. [5][6][7][8][9][10] These results indicate that NFs may impact a broad spectrum of applications in myocardial tissue engineering.Cell therapy is another promising approach to h...
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