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The role of erythropoietin (Epo) in myocardial repair after infarction remains inconclusive. We observed high Epo receptor (EPOR) expression in cardiac progenitor cells (CPCs). Therefore, we aimed to characterize these cells and elucidate their contribution to myocardial regeneration on Epo stimulation. High EPOR expression was detected during murine embryonic heart development followed by a marked decrease until adulthood. EPOR‐positive cells in the adult heart were identified in a CPC‐enriched cell population and showed coexpression of stem, mesenchymal, endothelial, and cardiomyogenic cell markers. We focused on the population coexpressing early (TBX5, NKX2.5) and definitive (myosin heavy chain [MHC], cardiac Troponin T [cTNT]) cardiomyocyte markers. Epo increased their proliferation and thus were designated as Epo‐responsive MHC expressing cells (EMCs). In vitro, EMCs proliferated and partially differentiated toward cardiomyocyte‐like cells. Repetitive Epo administration in mice with myocardial infarction (cumulative dose 4 IU/g) resulted in an increase in cardiac EMCs and cTNT‐positive cells in the infarcted area. This was further accompanied by a significant preservation of cardiac function when compared with control mice. Our study characterized an EPO‐responsive MHC‐expressing cell population in the adult heart. Repetitive, moderate‐dose Epo treatment enhanced the proliferation of EMCs resulting in preservation of post‐ischemic cardiac function. StemCells2014;32:2480–2491

The multiphasic regulation of the Wnt/β‐catenin canonical pathway is essential for cardiogenesis in vivo and in vitro. To achieve tight regulation of the Wnt/β‐catenin signaling, tissue‐ and cell‐specific coactivators and repressors need to be recruited. The identification of such factors may help to elucidate mechanisms leading to enhanced cardiac differentiation efficiency in vitro as well as promote regeneration in vivo. Using a yeast‐two‐hybrid screen, we identified four‐and‐a‐half‐LIM‐domain 2 (FHL2) as a cardiac‐specific β‐catenin interaction partner and activator of Wnt/β‐catenin‐dependent transcription. We analyzed the role of this interaction for early cardiogenesis in an in vitro model by making use of embryoid body cultures from mouse embryonic stem cells (ESCs). In this model, stable FHL2 gain‐of‐function promoted mesodermal cell formation and cell proliferation while arresting cardiac differentiation in an early cardiogenic mesodermal progenitor state. Mechanistically, FHL2 overexpression enhanced nuclear accumulation of β‐catenin and activated Wnt/β‐catenin‐dependent transcription leading to sustained upregulation of the early cardiogenic gene Igfbp5. In an alternative P19 cell model, transient FHL2 overexpression led to early activation of Wnt/β‐catenin‐dependent transcription, but not sustained high‐level of Igfbp5 expression. This resulted in enhanced cardiogenesis. We propose that early Wnt/β‐catenin‐dependent transcriptional activation mediated by FHL2 is important for the transition to and expansion of early cardiogenic mesodermal cells. Collectively, our findings offer mechanistic insight into the early cardiogenic code and may be further exploited to enhance cardiac progenitor cell activity in vitro and in vivo. STEMCELLS2013;31:928–940

Acute cardiogenic shock after myocardial infarction is associated with high in-hospital mortality attributable to persisting low-cardiac output. The Impella–EUROSHOCK-registry evaluates the safety and efficacy of the Impella-2.5–percutaneous left-ventricular assist device in patients with cardiogenic shock after acute myocardial infarction.

The adult heart has a uniform cellular response to adapt to injury after infarct or increased wall stress in chronic hypertension: hypertrophy of adult cardiomyocytes increases muscle fiber mass while at the same time apoptosis of cardiomyocytes may lead to further loss of contractile mass. The existence and quantitative amount of endogenous cardiac regeneration is currently under intense dispute, no clear picture has yet emerged. Recently, cardiac precursor cells and the signaling pathways controlling their differentiation in the adult organ have come into focus. In heart development, β-catenin was identified to play a biphasic role in cardiomyocyte differentiation. While initially WNT/β-catenin activation is required to commit mesenchymal cells to the cardiac lineage, downregulation of β-catenin is needed for cardiomyocyte differentiation at later stages. Recent genetic data published by our lab suggest β-catenin downregulation to be beneficial for adult cardiac remodeling. Here we discuss these data in the context of β-catenin´s role in adult cardiomyocyte hypertrophy, apoptosis and possibly regeneration.

Incubation of pulmonary A549 cells with D609, a phosphatidyl-choline specific phospholipase C (PC-PLC)-inhibitor, or the anti-oxidant, pyrrolidine dithiocarbamate (PTDC), markedly increased IL-1β-induced GM-CSF elaboration. This effect was observed at the mRNA level and could be partially reproduced by the protein synthesis inhibitor, cycloheximide. Following the peak in GM-CSF mRNA, the mRNA half-life (t1/2) was 0.5–1 h. This was increased to around 3 h by cycloheximide, whilst following D609 or PDTC treatment there was essentially no degradation. These data suggest the existence of inhibitory pathways that posttranscriptionally regulate GM-CSF expression via new protein synthesis and D609- and PDTC-sensitive steps. These observations may have important clinical implications. First, drugs that target gene induction may also knock out these inhibitory pathways to lessen their effect. Second, defects in such pathways could lead to overexpression of cytokines or growth factors and contribute to the pathogenesis of inflammatory or proliferative diseases.

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