Thymosin Beta 4 Is Dispensable for Murine Cardiac Development and Function

Department of Medicine, University of California-San Diego, La Jolla, 92093, USA.
Circulation Research (Impact Factor: 11.02). 12/2011; 110(3):456-64. DOI: 10.1161/CIRCRESAHA.111.258616
Source: PubMed

ABSTRACT Thymosin beta 4 (Tβ4) is a 43-amino acid factor encoded by an X-linked gene. Recent studies have suggested that Tβ4 is a key factor in cardiac development, growth, disease, epicardial integrity, and blood vessel formation. Cardiac-specific short hairpin (sh)RNA knockdown of tβ4 has been reported to result in embryonic lethality at E14.5-16.5, with severe cardiac and angiogenic defects. However, this shRNA tβ4-knockdown model did not completely abrogate Tβ4 expression. To completely ablate Tβ4 and to rule out the possibility of off-target effects associated with shRNA gene silencing, further studies of global or cardiac-specific knockouts are critical.
We examined the role of Tβ4 in developing and adult heart through global and cardiac specific tβ4-knockout mouse models.
Global tβ4-knockout mice were born at mendelian ratios and exhibited normal heart and blood vessel formation. Furthermore, in adult global tβ4-knockout mice, cardiac function, capillary density, expression of key cardiac fetal and angiogenic genes, epicardial marker expression, and extracellular matrix deposition were indistinguishable from that of controls. Tissue-specific tβ4-deficient mice, generated by crossing tβ4-floxed mice to Nkx2.5-Cre and αMHC-Cre, were also found to have no phenotype.
We conclude that Tβ4 is dispensable for embryonic viability, heart development, coronary vessel development, and adult myocardial function.

59 Reads
  • Source
    • "Importantly, at the present time thymosin β4 treatment has only been shown to induce the formation of arterioles and the ability of this approach to generate medium or large sized vessels is unknown. Furthermore, controversy has arisen regarding the developmental importance of thymosin β4 (Smart and Riley, 2013), with opposing data suggesting that thymosin β4 plays a key role in vascular smooth muscle cell recruitment to forming vessels and thus to vessel wall stability (Rossdeutsch et al., 2012), while others have argued that thymosin β4 plays no role whatsoever in vascular development (Banerjee et al., 2012, 2013). Additional research is required to clarify these issues and to explore whether thymosin β4-based therapies can provide a more robust arterial supply than has been demonstrated in the studies conducted to date (Smart et al., 2007, 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The history of revascularization for cardiac ischemia dates back to the early 1960's when the first coronary artery bypass graft procedures were performed in humans. With this 50year history of providing a new vasculature to ischemic and hibernating myocardium, a profound depth of experience has been amassed in clinical cardiovascular medicine as to what does, and does not work in the context of cardiac revascularization, alleviating ischemia and adequacy of myocardial perfusion. These issues are of central relevance to contemporary cell-based cardiac regenerative approaches. While the cardiovascular cell therapy field is surging forward on many exciting fronts, several well accepted clinical axioms related to the cardiac arterial supply appear to be almost overlooked by some of our current basic conceptual and experimental cell therapy paradigms. We present here information drawn from five decades of the clinical revascularization experience, review relevant new data on vascular formation via cell therapy, and put forward the case that for optimal cell-based cardiac regeneration due attention must be paid to providing an adequate vascular supply.
    Stem Cell Research 04/2014; 13(3). DOI:10.1016/j.scr.2014.04.009 · 3.69 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Over the last decade or so intensive research in cardiac stem cell biology has led to significant discoveries towards a potential therapy for cardiovascular disease; the main cause of morbidity and mortality in humans. The major goal within the field of cardiovascular regenerative medicine is to replace lost or damaged cardiac muscle and coronaries following ischemic disease. At present, de novo cardiomyocytes can be generated either in vitro, for cell transplantation or disease modelling using directed differentiation of embryonic stem cells or induced pluripotent stem cells, or in vivo via direct reprogramming of resident adult cardiac fibroblast or ectopic stimulation of resident cardiac stem or progenitor cells. A major bottleneck with all of these approaches is the low efficiency of cardiomyocyte differentiation alongside their relative functional immaturity. Chemical genetics, and the application of phenotypic screening with small molecule libraries, represent a means to enhance understanding of the molecular pathways controlling cardiovascular cell differentiation and, moreover, offer the potential for discovery of new drugs to invoke heart repair and regeneration. Here, we review the potential of chemical genetics in cardiac stem cell therapy, highlighting not only the major contributions to the field so far, but also the future challenges. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.
    British Journal of Pharmacology 03/2012; 169(2). DOI:10.1111/j.1476-5381.2012.01928.x · 4.84 Impact Factor
  • Source
    Circulation 04/2012; 125(14):1795-808. DOI:10.1161/CIRCULATIONAHA.111.040352 · 14.43 Impact Factor
Show more