Background-Despite widespread clinical use as a prognostic marker in ischemic heart disorders, the actual pathogenetic role of the short pentraxin, C-reactive protein, has not undergone stringent genetic testing because of evolutionary divergence between mouse and humans. The long pentraxin PTX3 is conserved in evolution, is expressed in the heart under inflammatory conditions, and is a candidate prognostic marker in acute myocardial infarction. It was therefore important to assess whether PTX3 plays a pathogenetic role in acute myocardial infarction. Methods and Results-In a model of acute myocardial infarction caused by coronary artery ligation and reperfusion, tissue mRNA expression and circulating levels of PTX3 increased. The interleukin-1R-MyD88 pathway plays a pivotal role in the induction of PTX3 transcript after ischemia. ptx3-deficient mice showed exacerbated heart damage (33% larger infarcts in null mice; Pϭ0.0047). Increased myocardial damage in ptx3-deficient mice was associated with a greater no-reflow area, increased neutrophil infiltration, decreased number of capillaries, and increased number of apoptotic cardiomyocytes. In addition, ptx3-deficient mice with acute myocardial infarction showed higher circulating levels of interleukin-6 and increased C3 deposition in lesional tissue. The phenotype was reversed by exogenous PTX3. Conclusions-Thus, PTX3 plays a nonredundant, regulatory, cardioprotective role in acute myocardial infarction in mice.Our results suggest that modulation of the complement cascade contributes to the cardioprotective function of PTX3.

Tumor growth and progression rely upon angiogenesis, which is regulated by pro-and antiangiogenic factors, including members of the semaphorin family. By analyzing 3 different mouse models of multistep carcinogenesis, we show here that during angiogenesis, semaphorin 3A (Sema3A) is expressed in ECs, where it serves as an endogenous inhibitor of angiogenesis that is present in premalignant lesions and lost during tumor progression. Pharmacologic inhibition of endogenous Sema3A during the angiogenic switch, the point when pretumoral lesions initiate an angiogenic phase that persists throughout tumor growth, enhanced angiogenesis and accelerated tumor progression. By contrast, when, during the later stages of carcinogenesis following endogenous Sema3A downmodulation, Sema3A was ectopically reintroduced into islet cell tumors by somatic gene transfer, successive waves of apoptosis ensued, first in ECs and then in tumor cells, resulting in reduced vascular density and branching and inhibition of tumor growth and substantially extended survival. Further, long-term reexpression of Sema3A markedly improved pericyte coverage of tumor blood vessels, something that is thought to be a key property of tumor vessel normalization, and restored tissue normoxia. We conclude, therefore, that Sema3A is an endogenous and effective antiangiogenic agent that stably normalizes the tumor vasculature.

Different cardiac stem/progenitor cells have been recently identified in the post-natal heart. We describe here the identification, clonal expansion and characterization of self-renewing progenitors that differ from those previously described for high spontaneous cardiac differentiation. Unique coexpression of endothelial and pericyte markers identify these cells as cardiac mesoangioblasts and allow prospective isolation and clonal expansion from the juvenile mouse ventricle. Cardiac mesoangioblasts express many cardiac transcription factors and spontaneously differentiate into beating cardiomyocytes that assemble mature sarcomeres and express typical cardiac ion channels. Cells similarly isolated from the atrium do not spontaneously differentiate. When injected into the ventricle after coronary artery ligation, cardiac mesoangioblasts efficiently generate new myocardium in the peripheral area of the necrotic zone, as they do when grafted in the embryonic chick heart. These data identify cardiac mesoangioblasts as committed progenitors, downstream of earlier stem/progenitor cells and suitable for the cell therapy of a subset of juvenile cardiac diseases. Cell Death and Differentiation (2008) Several acute or chronic cardiac diseases are characterized by progressive expansion of the left ventricular chamber, with replacement by fibrous deposition in the ventricular wall. One approach proposed for reverse myocardial remodeling is regeneration of cardiac myocytes using stem cells.1 On the basis of distinct cell surface markers such as Sca-1 or c-Kit, different cardiac stem-like cells have been isolated that can restore cardiac function after ischemic injury.2,3 None of these cells shows spontaneous cardiac differentiation and they also differentiate into other tissue types of the heart.2-5 On the other hand, Isl-1 expressing progenitors appear to be committed to cardiac differentiation but still require interactions with other cells for both proliferation and differentiation. 4 It is also becoming clear that a significant part of the beneficial effect that most of these cells exert on the infarcted heart is due to the secretion of factors that increase survival of residual myocardium and/or favor angiogenesis. 6 This was for example the case of embryonic mesoangioblasts whose transplantation resulted in a 50% recovery of cardiac function but whose differentiation into new cardiomyocytes was rare. 7Our recent work on mesoangioblasts isolated from postnatal skeletal muscle, 8,9 indicated that these cells, possibly because of a local commitment, exhibit efficient differentiation into skeletal muscle. On this basis, we isolated mesoangioblast-like cells from different regions of the post-natal mouse heart.Here we describe the isolation, through a specific explant culture method, of self-renewing committed cardiac progenitors from different regions of the juvenile heart. These cells, operationally termed 'cardiac mesoangioblasts', show a unique phenotype and high spontaneous cardiomyocyte differentiation; they can be e...