Heterochromatin protein 1 (HP1beta), a key component of condensed DNA, is strongly implicated in gene silencing and centromeric cohesion. Heterochromatin has been considered a static structure, stabilizing crucial aspects of nuclear organization and prohibiting access to transcription factors. We demonstrate here, by fluorescence recovery after photobleaching, that a green fluorescent protein-HP1beta fusion protein is highly mobile within both the euchromatin and heterochromatin of ex vivo resting murine T cells. Moreover, T cell activation greatly increased this mobility, indicating that such a process may facilitate (hetero)chromatin remodeling and permit access of epigenetic modifiers and transcription factors to the many genes that are consequently derepressed.

We analyzed the effect of conditional, ␣MHC-dependent genetic ␤-catenin depletion and stabilization on cardiac remodeling following experimental infarct. ␤-Catenin depletion significantly improved 4-week survival and left ventricular (LV) function (fractional shortening: CT ⌬ex3-6 : 24 ؎ 1.9%; ␤-cat ⌬ex3-6 : 30.2 ؎ 1.6%, P < 0.001). ␤-Catenin stabilization had opposite effects. No significant changes in adult cardiomyocyte survival or hypertrophy were observed in either transgenic line. Associated with the functional improvement, LV scar cellularity was altered: ␤-catenin-depleted mice showed a marked subendocardial and subepicardial layer of small cTnT pos cardiomyocytes associated with increased expression of cardiac lineage markers Tbx5 and GATA4. Using a Cre-dependent lacZ reporter gene, we identified a noncardiomyocyte cell population affected by ␣MHC-driven gene recombination localized to these tissue compartments at baseline. These cells were found to be cardiac progenitor cells since they coexpressed markers of proliferation (Ki67) and the cardiomyocyte lineage (␣MHC, GATA4, Tbx5) but not cardiac Troponin T (cTnT). The cell population overlaps in part with both the previously described c-kit pos and stem cell antigen-1 (Sca-1) pos precursor cell population but not with the Islet-1 pos precursor cell pool. An in vitro coculture assay of highly enriched (>95%) Sca-1 pos cardiac precursor cells from ␤-catenin-depleted mice compared to cells isolated from control littermate demonstrated increased differentiation toward ␣-actin pos and cTnT pos cardiomyocytes after 10 days (CT ⌬ex3-6 : 38.0 ؎ 1.0% ␣-actin pos ; ␤-cat ⌬ex3-6 : 49.9 ؎ 2.4% ␣-actin pos , P < 0.001). We conclude that ␤-catenin depletion attenuates postinfarct LV remodeling in part through increased differentiation of GATA4 pos /Sca-1 pos resident cardiac progenitor cells. D espite adaptive mechanisms including activation of cardiomyocyte survival pathways and hypertrophy, left ventricular (LV) remodeling often progresses to cardiac dilation and heart failure (1). Recently, the quantitative contribution of endogenous cardiac regeneration was found to account for at least 25% of cardiomyocytes in the infarct border zone (2). However, essential characteristics of this cardiac precursor cell pool, like signaling pathways directing differentiation and/or proliferation, are largely unknown.Transcription factors essential for embryonic cardiac development also affect adult cardiac remodeling in mice (3). Regulation of the Wnt/␤-catenin pathway differentially regulates embryonic cardiac progenitor cells prespecification, renewal, and differentiation in the cardiac mesoderm (4-7). Activation of the Wnt/␤-catenin pathway specifically stimulates Islet-1 cardiac progenitor cells proliferation while delaying differentiation. Conversely, increased expression of Wnt signaling inhibitors in ␣MHC pos cardiac precursor cells isolated from embryoid bodies lead to increased cardiomyocyte differentiation (8).We previously reported that downregulation of ␤-catenin in ...

Anticancer therapies, such as targeting of STAT3 or the use of anthracyclins (doxorubicin), can induce cardiomyopathy. In mice prone to developing heart failure as a result of reduced cardiac STAT3 expression (cardiomyocyte-restricted deficiency of STAT3) or treatment with doxorubicin, we observed impaired endothelial differentiation capacity of Sca-1(+) cardiac progenitor cells (CPCs) in conjunction with attenuated CCL2/CCR2 activation. Mice in both models also displayed reduced erythropoietin (EPO) levels in the cardiac microenvironment. EPO binds to CPCs and seems to be responsible for maintaining an active CCL2/CCR2 system. Supplementation with the EPO derivative CERA in a hematocrit-inactive low dose was sufficient to upregulate CCL2, restore endothelial differentiation of CPCs, and preserve the cardiac microvasculature and cardiac function in both mouse models. Thus, low-dose EPO treatment could potentially be exploited as a therapeutic strategy to reduce the risk of heart failure in certain treatment regimens.

The formation of primitive (embryonic) blood in vertebrates is mediated by spatio-temporally restricted signaling between different tissue layers. In Xenopus , in which primitive blood originates in the ventral blood island, this involves the secretion of bone morphogenetic protein (BMP) ligands by the ectoderm that signal to the underlying mesoderm during gastrulation. Using novel transgenic reporter lines, we report that the canonical Wnt/β-catenin pathway is also activated in the blood islands in Xenopus . Furthermore, Wnt-reporter activity was also detected in the blood islands of the mouse yolk sac. By using morpholino-mediated depletion in Xenopus , we identified Wnt4 as the ligand that is expressed in the mesoderm of the ventral blood island and is essential for the expression of hematopoietic and erythroid marker genes. Injection of an inducible Wnt-interfering construct further showed that, during gastrulation, Wnt/β-catenin signaling is required both in the mesoderm and in the overlying ectoderm for the formation of the ventral blood island. Using recombination assays with embryonic explants, we document that ectodermal BMP4 expression is dependent on Wnt4 signals from the mesoderm. Our results thus reveal a unique role for Wnt4-mediated canonical signaling in the formation and maintenance of the ventral blood island in Xenopus .