Signaling via the Tgf-β type I receptor Alk5 in heart development

University of Michigan, Department of Biologic and Materials Sciences, Ann Arbor, MI 48109, USA.
Developmental Biology (Impact Factor: 3.64). 09/2008; 322(1):208-18. DOI: 10.1016/j.ydbio.2008.07.038
Source: PubMed

ABSTRACT Trophic factors secreted both from the endocardium and epicardium regulate appropriate growth of the myocardium during cardiac development. Epicardially-derived cells play also a key role in development of the coronary vasculature. This process involves transformation of epithelial (epicardial) cells to mesenchymal cells (EMT). Similarly, a subset of endocardial cells undergoes EMT to form the mesenchyme of endocardial cushions, which function as primordia for developing valves and septa. While it has been suggested that transforming growth factor-betas (Tgf-beta) play an important role in induction of EMT in the avian epi- and endocardium, the function of Tgf-betas in corresponding mammalian tissues is still poorly understood. In this study, we have ablated the Tgf-beta type I receptor Alk5 in endo-, myo- and epicardial lineages using the Tie2-Cre, Nkx2.5-Cre, and Gata5-Cre driver lines, respectively. We show that while Alk5-mediated signaling does not play a major role in the myocardium during mouse cardiac development, it is critically important in the endocardium for induction of EMT both in vitro and in vivo. Moreover, loss of epicardial Alk5-mediated signaling leads to disruption of cell-cell interactions between the epicardium and myocardium resulting in a thinned myocardium. Furthermore, epicardial cells lacking Alk5 fail to undergo Tgf-beta-induced EMT in vitro. Late term mutant embryos lacking epicardial Alk5 display defective formation of a smooth muscle cell layer around coronary arteries, and aberrant formation of capillary vessels in the myocardium suggesting that Alk5 is controlling vascular homeostasis during cardiogenesis. To conclude, Tgf-beta signaling via Alk5 is not required in myocardial cells during mammalian cardiac development, but plays an irreplaceable cell-autonomous role regulating cellular communication, differentiation and proliferation in endocardial and epicardial cells.

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    • "We found that only a small percentage of cells expressing WT1 were present in the epicardium, the subepicardium and the infarcted area; however, the number of WT1 pos cells within the infarcted area was increased in AICAR-treated hearts (Supplemental Fig. 2). As TGF-β1 stimulates epicardial-to-mesenchymal transition (EMT) [33] and AICAR augments TGF-β1 signaling [9], the activated TGF-β1/AMPK pathway may account for the elevated EMT in AICAR-treated hearts. Because of the small portion of WT1 pos cells in the infracted area they might be contributing to a minor extent to fibroblast formation in the aging heart as suggested by others [32] "
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    ABSTRACT: We have demonstrated that scar formation after myocardial infarction (MI) is associated with an endogenous pool of CD44(pos)CD45(neg) multipotential mesenchymal stem cells (MSC). MSC differentiate into fibroblasts secreting collagen that forms a scar and mature into myofibroblasts that express alpha smooth muscle actin (α-SMA) that stabilizes the scar. In the aging mouse, cardiac repair after MI is associated with impaired differentiation of MSC; MSC derived from aged hearts form dysfunctional fibroblasts that deposit less collagen in response to transforming growth factor beta-1 (TGF-β1) and poorly mature into myofibroblasts. We found in vitro that the defect in myofibroblast maturation can be remedied by AICAR, which activates non-canonical TGF-β signaling through AMP-activated protein kinase (AMPK). In the present study, we injected aged mice with AICAR and subjected them to 1h occlusion of the left anterior descending artery (LAD) and then reperfusion for up to 30 days. AICAR-dependent AMPK signaling led to mobilization of an endogenous CD44(pos)CD45(neg) MSC and its differentiation towards fibroblasts and myofibroblasts in the infarct. This was accompanied by enhanced collagen deposition and collagen fiber maturation in the scar. The AICAR-treated group has demonstrated reduced adverse remodeling as indicated by improved apical end diastolic dimension but no changes in ejection fraction and cardiac output were observed. We concluded that these data indicate the novel, previously not described role of AMPK in the post-MI scar formation. These findings can potentially lead to a new therapeutic strategy for prevention of adverse remodeling in the aging heart.
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    • "Concerns have been raised regarding the lineage tracing of epicardial cells by this method. The Cre-mice available include, Wt1-Cre, TBX18-Cre and Gata5-Cre, that do appear to allow epicardial specific expression when analyzing limited areas of the heart at certain stages (Cai et al., 2008; Sridurongrit et al., 2008; Zhou et al., 2008). However, these may not be as specific as desired. "
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    • "Quite paradoxically, the cardiovascular tissues from Loeys-Dietz syndrome patients, which have loss-of-function TGFBR2/1 mutations, show elevated pSMAD2 and TGFβ target gene expression (Loeys et al. 2005;Loeys et al. 2006). Although Tgfbr2 and Tgfbr1 conditional deletion in mice has revealed important tissue-specific roles of these receptors in cardiovascular development, these studies have failed to generate any direct information about their function in adult cardiovascular tissues and in the pathogenesis of cardiovascular diseases (Jiao et al. 2006;Choudhary et al. 2009;Sridurongrit et al. 2008;Robson et al. 2010) (Langlois et al. 2010). Overall, the cell autonomous and non-autonomous aspects of the genetic mutations in TGFB receptor genes remain unclear. "
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