Thymosin Beta-4, also called TB4 and TB500, is a 40-44 amino acid thymic peptide and signaling protein with diverse functions throughout the body. TB4 is nearly ubiquitous in living tissue. Initially discovered in the 1960s by Goldstein acting in its role as an actin-sequestration agent, later research revealed its role in wound-healing, neurological regeneration, cardiac regeneration, immune function, cell migration, and blood vessel formation. In the decades after its discovery TB4 has been recognized as having therapeutic potential for traumatic brain injury (TBI), wound healing, skeletal muscle recovery, sepsis, central nervous system (CNS) diseases, and myocardial infarction, as well as performance enhancement in racehorses.
According to Bubb et al (2003), extracellular or serum unbound TB4 is probably unfolded and able to ineract with multiple receptors and form complexes with other ligands (receptor-binding proteins) to interact with a greater number of receptors:
Thymosin beta 4 is largely unfolded or perhaps completely unfolded in solution. Based on the paradigm introduced by Wright and Dyson (1999) that unfolded proteins may have multiple functions based on their ability to recognize numerous ligands, the flexible structure of thymosin beta 4 may facilitate the recognition of a variety of molecular targets, thus explaining the plethora of functions attributed to thymosin beta 4. Furthermore, if multiple ligands bind to thymosin beta 4, then it is possible that thymosin beta 4 has a unique integrative function that links the actin cytoskeleton to important immune and cell growth-signaling cascades.
Tokura et al (2011) find that a TB4’s chemoattractant property is responsible, or partially responsible, for its effects on skeletal muscle regeneration and healing:
…we showed that primary myoblasts and myocytes derived from muscle satellite cells of adult mice were chemoattracted to sulphoxized form of Tβ4. These data indicate that muscle injury enhances the local production of Tβ4, thereby promoting the migration of myoblasts to facilitate skeletal muscle regeneration.
The same authors also found an accelerated rate of dermal wound healing.
The pro-healing effects of TB4 on tissue are also mediated by other mechanisms, including antifibrotic mechanisms that help reduce scarring and help healthy tissue regenerate. Goldstein (2012) writes that
after injury, thymosin β(4), is released by platelets, macrophages and many other cell types to protect cells and tissues from further damage and reduce apoptosis, inflammation and microbial growth. Thymosin β(4) binds to actin and promotes cell migration, including the mobilization, migration, and differentiation of stem/progenitor cells, which form new blood vessels and regenerate the tissue. Thymosin β(4) also decreases the number of myofibroblasts in wounds, resulting in decreased scar formation and fibrosis
TB4 also exhibits this antifibrotic effect in the myocardium when administered prior to myocardial infarction. According to Kumar and Gupta (2011) “findings indicate that Tβ4 selectively targets and upregulates catalase, Cu/Zn-SOD and Bcl(2), thereby, preventing H(2)O(2)-induced profibrotic changes in the myocardium”.
Zhou et al found that when applied after MI, TB4 exhibited some, but not all, effects seen during pretreatment:
Recently it was reported that in mice pretreated with thymosin beta 4 (TB4) and subsequently subjected to experimental MI, a subset of epicardial cells differentiated into cardiomyocytes. In clinical settings, epicardial priming with TB4 prior to MI is impractical. … we found post-MI TB4 treatment significantly increased the thickness of epicardium and coronary capillary density. However, epicardium-derived cells did not adopt cardiomyocyte fate, nor did they migrate into myocardium to become coronary endothelial cells. Our result thus indicates that TB4 treatment after MI does not alter epicardial cell fate to include the cardiomyocyte lineage…
In rats with TBI, TB4 treatment "did not affect lesion volume but ... reduced hippocampal cell loss, enhanced angiogenesis and neurogenesis in the injured cortex and hippocampus...and significantly improved sensorimotor functional recovery and spatial learning." Xiong et al concluded that the data "demonstrate that delayed administration...improves histological and functional outcomes in rats...indicating...therapeutic potential for patients with TBI."
Goldstein, AL. History of the Discovery of the Thymosins. Annals NY Acad Vol. 1112. Oct 2007.
Bubb MR. Thymosin beta 4 interactions. Vitam Horm. 2003;66:297-316.
Goldstein AL, Hannappel E, Sosne G, Kleinman HK. Thymosin β4: a multi-functional regenerative peptide. Basic properties and clinical applications. Expert Opin Biol Ther. 2012 Jan;12(1):37-51.
Tokura Y et al. (January 2011). Muscle injury-induced thymosin β4 acts as a chemoattractant for myoblasts. J Biochem. 149(1):43-8.
Kumar S, Gupta S. Thymosin beta 4 prevents oxidative stress by targeting antioxidant and anti-apoptotic genes in cardiac fibroblasts. PLoS One. Oct 2011;6(10):e26912.
 Zhou B, et al. Thymosin beta 4 treatment after myocardial infarction does not reprogram epicardial cells into cardiomyocytes. J Mol Cell Cardiol. Aug 2011.
 Xiong Y, Mahmood A, et al.. Treatment of traumatic brain injury with thymosin B4 in rats. J Neurosurg. 114(1):102-15. Jan 2011.