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1.  Thymosin β4 in Vascular Development 
Circulation research  2013;112(3):e29-e30.
doi:10.1161/CIRCRESAHA.112.300555
PMCID: PMC3978174  PMID: 23371906
2.  The epicardium as a candidate for heart regeneration 
Future cardiology  2012;8(1):53-69.
The mammalian heart loses its regenerative capacity during early postnatal stages; consequently, individuals surviving myocardial infarction (MI) are at risk of heart failure due to excessive fibrosis and maladaptive remodelling. There is an urgent need, therefore, to develop novel therapies for myocardial and coronary vascular regeneration. The epicardium-derived cells (EPDCs) present a tractable resident progenitor source with the potential to stimulate neovasculogenesis and contribute de novo cardiomyocytes. The ability to revive ordinarily dormant EPDCs lies in the identification of key stimulatory factors, such as Tβ4, and elucidation of the molecular cues used in the embryo to orchestrate cardiovascular development. MI injury signalling reactivates the adult epicardium; understanding the timing and magnitude of these signals will enlighten strategies for myocardial repair.
doi:10.2217/fca.11.87
PMCID: PMC3977139  PMID: 22185446
Epicardium; EPDCs; neovascularisation; myocardial regeneration; cardiac development; epicardial signalling; injury signalling; Thymosin β4
3.  Thymosin β4-sulfoxide attenuates inflammatory cell infiltration and promotes cardiac wound healing 
Nature communications  2013;4:2081.
The downstream consequences of inflammation in the adult mammalian heart are formation of a non-functional scar, pathological remodelling and heart failure. In zebrafish, hydrogen peroxide (H2O2) released from a wound is the initial instructive chemotactic cue for the infiltration of inflammatory cells, however, the identity of a subsequent resolution signal(s), to attenuate chronic inflammation, remains unknown. Here we reveal that Thymosin β4-Sulfoxide inhibits interferon-γ, and increases monocyte dispersal and cell death, lies downstream of H2O2 in the wounded fish and triggers depletion of inflammatory macrophages at the injury site. This function is conserved in the mouse and observed after cardiac injury, where it promotes wound healing and reduced scarring. In human T cell/CD14+ monocyte co-cultures, Tβ4-SO inhibits IFN-γ and increases monocyte dispersal and cell death, likely by stimulating superoxide production. Thus, Tβ4-SO is a putative target for therapeutic modulation of the immune response, resolution of fibrosis and cardiac repair.
doi:10.1038/ncomms3081
PMCID: PMC3797509  PMID: 23820300
4.  De novo cardiomyocytes from within the activated adult heart after injury 
Nature  2011;474(7353):640-644.
A significant bottleneck in cardiovascular regenerative medicine is the identification of a viable source of stem/progenitor cells that could contribute new muscle after ischaemic heart disease and acute myocardial infarction1. A therapeutic ideal—relative to cell transplantation—would be to stimulate a resident source, thus avoiding the caveats of limited graft survival, restricted homing to the site of injury and host immune rejection. Here we demonstrate in mice that the adult heart contains a resident stem or progenitor cell population, which has the potential to contribute bona fide terminally differentiated cardiomyocytes after myocardial infarction. We reveal a novel genetic label of the activated adult progenitors via re-expression of a key embryonic epicardial gene, Wilm’s tumour 1 (Wt1), through priming by thymosin β4, a peptide previously shown to restore vascular potential to adult epicardium-derived progenitor cells2 with injury. Cumulative evidence indicates an epicardial origin of the progenitor population, and embryonic reprogramming results in the mobilization of this population and concomitant differentiation to give rise to de novo cardiomyocytes. Cell transplantation confirmed a progenitor source and chromosome painting of labelled donor cells revealed transdifferentiation to a myocyte fate in the absence of cell fusion. Derived cardiomyocytes are shown here to structurally and functionally integrate with resident muscle; as such, stimulation of this adult progenitor pool represents a significant step towards residentcell-based therapy in human ischaemic heart disease.
doi:10.1038/nature10188
PMCID: PMC3696525  PMID: 21654746
5.  Prox1 maintains muscle structure and growth in the developing heart 
Development (Cambridge, England)  2008;136(3):495-505.
Impaired cardiac muscle growth and aberrant myocyte arrangement underlie congenital heart disease and cardiomyopathy. We show that cardiac-specific inactivation of the homeobox transcription factor Prox1 results in disruption of the expression and localisation of sarcomeric proteins, gross myofibril disarray and growth retarded hearts. Furthermore, we demonstrate that Prox1 is required for direct transcriptional regulation of structural proteins α-actinin, N-RAP and Zyxin which collectively function to maintain an actin-α-actinin interaction as the fundamental association of the sarcomere. Aspects of abnormal heart development and manifestation of a subset of muscular-based disease have previously been attributed to mutations in key structural proteins. Our study demonstrates an essential requirement for direct transcriptional regulation of sarcomere integrity, in the context of enabling fetal cardiomyocyte hypertrophy, maintenance of contractile function and progression towards inherited or acquired myopathic disease.
doi:10.1242/dev.030007
PMCID: PMC2655234  PMID: 19091769
Prox1; heart development; myocardium; sarcomere; hypertrophy; myopathy
6.  Differential Regulation of Hand1 Homodimer and Hand1-E12 Heterodimer Activity by the Cofactor FHL2 
Molecular and Cellular Biology  2004;24(22):9835-9847.
The basic helix-loop-helix (bHLH) factor Hand1 plays an essential role in cardiac morphogenesis, and yet its precise function remains unknown. Protein-protein interactions involving Hand1 provide a means of determining how Hand1-induced gene expression in the developing heart might be regulated. Hand1 is known to form either heterodimers with near-ubiquitous E-factors and other lineage-restricted class B bHLH proteins or homodimers with itself in vitro. To date, there have been no reported Hand1 protein interactions involving non-bHLH proteins. Heterodimer-versus-homodimer choice is mediated by the phosphorylation status of Hand1; however, little is known about the in vivo function of these dimers or, importantly, how they are regulated. In an effort to understand how Hand1 activity in the heart might be regulated postdimerization, we have investigated tertiary Hand1-protein interactions with non-bHLH factors. We describe a novel interaction of Hand1 with the LIM domain protein FHL2, a known transcriptional coactivator and corepressor expressed in the developing cardiovascular system. FHL2 interacts with Hand1 via the bHLH domain and is able to repress Hand1/E12 heterodimer-induced transcription but has no effect on Hand1/Hand1 homodimer activity. This effect of FHL2 is not mediated either at the level of dimerization or via an effect of Hand1/E12 DNA binding. In summary, our data describe a novel differential regulation of Hand1 heterodimers versus homodimers by association of the cofactor FHL2 and provide insight into the potential for a tertiary level of control of Hand1 activity in the developing heart.
doi:10.1128/MCB.24.22.9835-9847.2004
PMCID: PMC525463  PMID: 15509787
7.  Identification of Thymosin β4 as an effector of Hand1-mediated vascular development 
Nature Communications  2010;1(4):1-10.
The bHLH transcription factor Hand1 (Heart and neural crest-derived transcript-1) has a fundamental role in cardiovascular development; however, the molecular mechanisms have not been elucidated. In this paper we identify Thymosin β4 (Tβ4/Tmsb4x), which encodes an actin monomer-binding protein implicated in cell migration and angiogenesis, as a direct target of Hand1. We demonstrate that Hand1 binds an upstream regulatory region proximal to the promoter of Tβ4 at consensus Thing1 and E-Box sites and identify both activation and repression of Tβ4 by Hand1, through direct binding within either non-canonical or canonical E-boxes, providing new insight into gene regulation by bHLH transcription factors. Hand1-mediated activation of Tβ4 is essential for yolk sac vasculogenesis and embryonic survival, and administration of synthetic TB4 partially rescues yolk sac capillary plexus formation in Hand1-null embryos. Thus, we identify an in vivo downstream target of Hand1 and reveal impaired yolk sac vasculogenesis as a primary cause of early embryonic lethality following loss of this critical bHLH factor.
The Hand1 transcription factor plays a central role in cardiovascular development. Here the authors demonstrate that Hand1 regulates thymosin β4 and that the delivery of synthetic thymosin β4 can rescue some of the vascular defects in Hand1 null mouse embryos.
doi:10.1038/ncomms1041
PMCID: PMC2963826  PMID: 20975697

Results 1-7 (7)