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.
Background-We identified an interleukin-1 receptor family member, ST2, as a gene markedly induced by mechanical strain in cardiac myocytes and hypothesized that ST2 participates in the acute myocardial response to stress and injury. Methods and Results-ST2 mRNA was induced in cardiac myocytes by mechanical strain (4.7Ϯ0.9-fold) and interleukin-1 (2.0Ϯ0.2-fold). Promoter analysis revealed that the proximal and not the distal promoter of ST2 is responsible for transcriptional activation in cardiac myocytes by strain and interleukin-1. In mice subjected to coronary artery ligation, serum ST2 was transiently increased compared with unoperated controls (20.8Ϯ4.4 versus 0.8Ϯ0.8 ng/mL, PϽ0.05). Soluble ST2 levels were increased in the serum of human patients (Nϭ69) 1 day after myocardial infarction and correlated positively with creatine kinase (rϭ0.41, PϽ0.001) and negatively with ejection fraction (Pϭ0.02). Conclusions-These data identify ST2 release in response to myocardial infarction and suggest a role for this innate immune receptor in myocardial injury.
Background-Local delivery of chemotactic factors represents a novel approach to tissue regeneration. However, successful chemokine protein delivery is challenged by barriers including the rapid diffusion of chemokines and cleavage of chemokines by proteases that are activated in injured tissues. Stromal cell-derived factor-1 (SDF-1) is a well-characterized chemokine for attracting stem cells and thus a strong candidate for promoting regeneration. However, SDF-1 is cleaved by exopeptidases and matrix metalloproteinase-2, generating a neurotoxin implicated in some forms of dementia. Methods and Results-We designed a new chemokine called S-SDF-1(S4V) that is resistant to matrix metalloproteinase-2 and exopeptidase cleavage but retains chemotactic bioactivity, reducing the neurotoxic potential of native SDF-1. To deliver S-SDF-1(S4V), we expressed and purified fusion proteins to tether the chemokine to self-assembling peptides, which form nanofibers and allow local delivery. Intramyocardial delivery of S-SDF-1(S4V) after myocardial infarction recruited CXCR4 ϩ /c-Kit ϩ stem cells (46Ϯ7 to 119Ϯ18 cells per section) and increased capillary density (from 169Ϯ42 to 283Ϯ27 per 1 mm 2 ). Furthermore, in a randomized, blinded study of 176 rats with myocardial infarction, nanofiber delivery of the protease-resistant S-SDF-1(S4V) improved cardiac function (ejection fraction increased from 34.0Ϯ2.5% to 50.7Ϯ3.1%), whereas native SDF-1 had no beneficial effects. Conclusions-The combined advances of a new, protease-resistant SDF-1 and nanofiber-mediated delivery promoted recruitment of stem cells and improved cardiac function after myocardial infarction. These data demonstrate that driving chemotaxis of stem cells by local chemokine delivery is a promising new strategy for tissue regeneration. (Circulation.
Background-ST2 is a member of the interleukin-1 receptor family with a soluble form that is markedly upregulated on application of biomechanical strain to cardiac myocytes. Circulating ST2 levels are elevated in the setting of acute myocardial infarction, but the predictive value of ST2 independent of traditional clinical factors and of an established biomarker of biomechanical strain, N-terminal prohormone B-type natriuretic peptide (NT-proBNP), has not been established. Methods and Results-We measured ST2 at baseline in 1239 patients with ST-elevation myocardial infarction from the CLopidogrel as Adjunctive ReperfusIon TherapY-Thrombolysis in Myocardial Infarction 28 (CLARITY-TIMI 28) trial. Per trial protocol, patients were to undergo coronary angiography after 2 to 8 days and were followed up for 30 days for clinical events. In contrast to NT-proBNP, ST2 levels were independent of clinical factors potentially related to chronic increased left ventricular wall stress, including age, hypertension, prior myocardial infarction, and prior heart failure; levels also were only modestly correlated with NT-proBNP (rϭ0.14). After adjustment for baseline characteristics and NT-proBNP levels, an ST2 level above the median was associated with a significantly greater risk of cardiovascular death or heart failure (third quartile: adjusted odds ratio, 1.42; 95% confidence interval, 0.68 to 3.57; fourth quartile: adjusted odds ratio, 3.57; 95% confidence interval, 1.87 to 6.81; PϽ0.0001 for trend). When both ST2 and NT-proBNP were added to a model containing traditional clinical predictors, the c statistic significantly improved from 0.82 (95% confidence interval, 0.77 to 0.87) to 0.86 (95% confidence interval, 0.81 to 0.90) (Pϭ0.017). Conclusions-In ST-elevation myocardial infarction, high baseline ST2 levels are a significant predictor of cardiovascular death and heart failure independently of baseline characteristics and NT-proBNP, and the combination of ST2 and NT-proBNP significantly improves risk stratification. These data highlight the prognostic value of multiple, complementary biomarkers of biomechanical strain in ST-elevation myocardial infarction.
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