Cardiac interstitial cells express GATA4 and control dedifferentiation and cell cycle re-entry of adult cardiomyocytes

Department of Biomedical Sciences, University of Padua, Padua, Italy.
Journal of Molecular and Cellular Cardiology (Impact Factor: 4.66). 05/2009; 46(5):653-62. DOI: 10.1016/j.yjmcc.2008.12.010
Source: PubMed


Interstitial cells of the adult rat heart were characterized with respect to i) expression of cardiac markers of commitment and differentiation, ii) myogenic potential in vitro and iii) ability to modulate cardiomyocyte differentiation state. We demonstrate for the first time that fibroblasts and a proportion of pericytes in the adult rat heart express the transcription factor GATA4. This appears to be a peculiar property of the heart. Fibroblasts that are also derived from the splanchnopleuric mesoderm, such as those of the gut, or fibroblasts of different embryological origin, such as those of skin and skeletal muscle, lack this property. Of note, a nestin+/GATA4+ putative stem cell population is also detected in the adult heart. GATA4+ cardiac interstitial cells do not display myogenic potential in vitro. However, cardiac fibroblasts, but not skin fibroblasts, stimulate dedifferentiation of adult cardiomyocytes and their re-entry into the cell cycle in vitro, as demonstrated by the high number of cardiomyocytes expressing Ki67, phosphorylated histone H3 (H3P) and incorporating 5-bromodeoxiuridine (BrdU) in the co-cultures. In conclusion, cardiac fibroblasts have peculiar expression of myogenic transcription factors, a property that may have an impact for reprogramming these cells to the myogenic differentiation. In addition, they are able to modulate the behavior of adult cardiomyocytes, a property that may be used to promote dedifferentiation and proliferation of cardiac cells in the damaged myocardium.

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    • "Recent data from our group have highlighted that peculiar stromal cells, called telocytes, mediate myocardial compaction in vitro and regulate the ventricular wall organization during mouse heart development [18]. Further support to the sculpturing role of stromal cells in heart development comes from the in vitro demonstration that embryonic, but not adult, fibroblasts are able to promote cardiomyocyte engraftment in a three-dimensional collagen matrix [19], selectively express the GATA-4 cardiac transcriptional factor [20], and activate the dedifferentiation and cell cycle re-entry of adult cardiomyocytes [21]. "
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    • "Of further interest are the separate populations of proliferating GATA4 and Islet1 expressing cells in and around the area of regeneration that is not co-localized with cardiomyocyte markers. This indicates that there could be a population of cardiac progenitors with an earlier developmental phenotype up-regulated during the regeneration phase (Laugwitz et al., 2008; Zaglia et al., 2009). From where these cells derive still needs to be elucidated but we believe this is the first time that Islet1 positive cells can be linked to cardiac regeneration in vivo. "
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