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


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.

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    • "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). "
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    • "Remarkably, a small subpopulation of Tb4-stimulated EPDCs also differentiates into cardiomyocytes, suggesting a potential for heart repair and regeneration (Smart et al., 2011). While a recent study in the mouse, following global knockout of Tb4, suggested that it is not crucial for survival (Banerjee et al., 2011), this is countered by a previous in vivo RNAi knock-down model, which revealed an essential role for Tb4 in coronary vascular development (Smart et al., 2007), illustrating the more severe instantaneous loss of function with RNAi versus targeting through the germline, which itself can be subject to compensation . That said gain of function, via the ectopic administration of synthetic Tb4, clearly establishes a potential role for Tb4 in heart repair. "
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