Thymosin beta 4 - small molecule with big impact?

Thymosin beta 4 is dispensable for embryonic viability, heart function and development.

Insights into the functions of molecular factors involved in cardiovascular development and function can improve our understanding of the homeostatic and diseased heart. Thymosin beta 4 is a 43–amino acid factor encoded by an X-linked gene. Recent studies have suggested that Thymosin beta 4 is a key factor in cardiac development, growth, disease, epicardial integrity, and blood vessel formation. Cardiac-specific short hairpin (sh)RNA knockdown of Thymosin beta 4 has been reported to result in embryonic lethality at E14.5–16.5, with severe cardiac and angiogenic defects. However, this shRNA Thymosin beta 4-knockdown model did not completely abrogate Thymosin beta 4 expression.
To completely ablate Thymosin beta 4 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. Therefore, we established and examined the role of Thymosin beta 4 in developing and adult heart through global and cardiac specific Thymosin beta 4-knockout mouse models.

Our studies found that global Thymosin beta 4-knockout mice were born at mendelian ratios and exhibited normal heart and blood vessel formation. Furthermore, in adult global Thymosin beta 4-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. Moreover, tissue-specific Thymosin beta 4-deficient mice, generated by crossing Thymosin beta 4-floxed mice to Nkx2.5-Cre and alpha-MHC-Cre, were also found to have no phenotype. From these data we conclude that Thymosin beta 4 is dispensable for embryonic viability, heart function and development. We are currently using these models to examine the role of Thymosin beta 4in cardiovascular disease models.

The manuscript for the Thymosin beta 4 study was published in the Journal Circulation Research >

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Research Commentary

Thymosin beta4 Is Not Required for Embryonic Viability or Vascular Development

Recently, a manuscript proposed important functions for thymosin beta-4 in the development and stability of vascular vessels. These data are in direct contrast to our published global and cardiac-specific Tβ4-knockout lines. Thus, the role of Tβ4 needed to be clarified to understand its importance in cardiovascular development. Analysis of our Thymosin beta-4 global, cardiac- and endothelial-specific knockout models demonstrated that Tβ4 is dispensable for embryonic viability and vascular development. Read the full research commentary here, and the response by Smart & Riley here (Subscription may be required).

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Indro Banerjee, PhD
Lead postdoctoral scientist on the TB4 project.