Although cell fusion between rCMs and MSCs was detectable, the very low frequency (0.7%) could not account for the phenotype of the GFP ؉ MSCs. In conclusion, we have identified an MSC population displaying plasticity toward the cardiomyocyte lineage while retaining mesenchymal stromal cell properties, including a nonexcitable electrophysiological phenotype. The demonstration of an MSC population coexpressing cardiac and stromal cell markers may explain conflicting results in the literature and indicates the need to better understand the effects of MSCs on myocardial injury. STEM

Cardiac hypertrophy and dilation are mediated by neuroendocrine factors and/or mitogens as well as through internal stretch-and stresssensitive signaling pathways, which in turn transduce alterations in cardiac gene expression through specific signaling pathways. The transcription factor family known as myocyte enhancer factor 2 (MEF2) has been implicated as a signal-responsive mediator of the cardiac transcriptional program. For example, known hypertrophic signaling pathways that utilize calcineurin, calmodulin-dependent protein kinase, and MAPKs can each affect MEF2 activity. Here we demonstrate that MEF2 transcription factors induced dilated cardiomyopathy and lengthening of myocytes. Specifically, multiple transgenic mouse lines with cardiac-specific overexpression of MEF2A or MEF2C presented with cardiomyopathy at base line or were predisposed to more fulminant disease following pressure overload stimulation. The cardiomyopathic response associated with MEF2A and MEF2C was not further altered by activated calcineurin, suggesting that MEF2 functions independently of calcineurin in this response. In cultured cardiomyocytes, MEF2A, MEF2C, and MEF2-VP16 overexpression induced sarcomeric disorganization and focal elongation. Mechanistically, MEF2A and MEF2C each programmed similar profiles of altered gene expression in the heart that included extracellular matrix remodeling, ion handling, and metabolic genes. Indeed, adenoviral transfection of cultured cardiomyocytes with MEF2A or of myocytes from the hearts of MEF2A transgenic adult mice showed reduced transient outward K ؉ currents, consistent with the alterations in gene expression observed in transgenic mice and partially suggesting a proximal mechanism underlying MEF2-dependent cardiomyopathy.Myocyte enhancer factor 2 (MEF2) 5 was originally identified as a muscle-enriched DNA binding activity from differentiated myotubes, although it is now recognized to be widely distributed in most tissues (1). MEF2 DNA binding activity consists of homo-and heterodimers of four separate gene products in mammals, referred to as Mef2a-d (2, 3). MEF2 dimers bind to the consensus sequence CTA(A/T) 4 TAG present in the 5Ј-transcriptional regulatory regions of most skeletal and cardiac muscle structural genes characterized to date (2, 3). In general, Mef2a-d genes are widely expressed in the adult vertebrate organism, although a number of specific regulatory functions have been identified in immune, skeletal muscle, cardiac muscle, and neuronal cells (4 -7).MEF2 factors are related to another MADS box-containing transcription factor known as serum response factor (SRF) (8). Similar to SRF, members of the MEF2 family have been implicated in regulating inducible gene expression in response to mitogen and/or stress stimulation. In the heart, myocytes undergo developmental and pathophysiological hypertrophy in response to neuroendocrine, mitogen, and stress stimulation. Such stimuli activate intracellular signal transduction cascades, resulting in the modification of transcription...