What is Thymosin Beta-4?

The beta-thymosins (b-thymosins) comprise a family of structurally related, highly conserved amino acid sequences in species ranging from mammals to echinoderms. Of the 16 known family members, thymosin β4 (Tb4), thymosin β10 (Tb10), and thymosin β15 (Tb15) are found in man.

Thymosin beta-4 (TB4) is a 43 amino acid, 5kDa polypeptide that is an important mediator of cell proliferation, migration, and differentiation. TB4 is the most abundant member of the β- thymosin family in mammalian tissue and is regarded as the main G-actin sequestering peptide. It is found in all tissues and cell types except red blood cells. Thymosin beta-4 is angiogenic and can promote endothelial cell migration and adhesion, and angiogenesis. TB4 also accelerates wound healing and reduces inflammation and scarring when applied in dermal wound-healing assays.

 

Beta thymosins bind and sequester monomeric actin, thus preventing actin polymerization and formation of filamentous actin. Actin is a vital component of cell structure and movement. Actin is involved in many important non-muscle cellular processes, including cell locomotion, chemotaxis, phagocytosis, and cytokinesis. Of the thousands of proteins present in cells, actin makes up to 10% of the total proteins in a cell, representing a major role in the genetic makeup of the cell.

Animal studies of disease and repair when using thymosin beta-4, the major actin-sequestering molecule in mammalian cells, have provided a base for the ongoing multicenter clinical trials for wound healing, including dermal, corneal, and cardiac. TB4 has multiple biological activities, which include down-regulation of inflammatory chemokines and cytokines, and promotion of cell migration, blood vessel formation, cell survival, and stem cell maturation.

Thymosin beta-4 also inhibits inflammation, microbial growth, scar formation (by reducing the level of myofibroblasts), and apoptosis, and protects cells from cytotoxic damage, including glutamate neuronal toxicity. In addition, it binds to G-actin, blocks actin polymerization, and is released with factor X by platelets. These activities contribute to the multiple wound healing properties that have been reported in animal and human studies.

 

What have Research Studies Shown?

Thymosin beta 4 is a synthetic peptide found in most cells and tissues.

• Originally isolated from calf thymus

• Main intracellular G-actin sequestering peptide

• Up-regulates actin

• Forms a ternary complex with actin and profilin

• Increases cells involved in healing

• Improves cell migration to site of injury

• Promotes matrix metalloproteinase expression during wound repair

• Promotes angiogenesis

• Cytoprotective

• Helps decrease scar tissue formation

• Improves T cells

• Used for clinical conditions where soft tissue recovery or immune support is needed

• Sports/athletic injury

• Soft tissue repair

• Tendon/ligament/muscle repair

• Pressure ulcers / venous stasis ulcers

• Immune support (as monotherapy or in conjunction with Thymosin alpha 1)

• Brain issues if autoimmunity suspected

• Multiple sclerosis

• Ischemic stroke

• Spinal cord injuries

• TBI; concussion support (in conjunction with BPC 157)

• Sepsis

• Dry eye disorders

• Ocular tissue injuries including corneal wound healing and repair

• Chemical burns

• Diabetes

• Corneal transplants

• Cardioprotective

• NAFLD – non-alcoholic fatty liver disease

• Lung inflammation / fibrosis

• May improve hair growth

 

Thymosin Beta-4 in Research (Expanded)

Ocular

TB4 promotes complete and faster corneal healing than saline alone or prescription agents (doxycycline and cyclosporine) in various animal models of eye injury. In human trials, TB4 eye drops improve both the signs and symptoms of moderate to severe dry eye with effects lasting beyond the treatment period. Thymosin beta-4 has also reported efficacy in three phase 2 clinical ocular trials with no evidence of any adverse events. See table 1 below for a summary of corneal wound healing applications.

Table 1: Corneal Wound Healing Applications

Non Medical Application

• Chemical Burns

• Patients undergoing photorefractive keratectomy (PRK)

Medical Applications

• Stage 2 patients (Mackie classification) with neurotrophic keratitis

• Patients with recurrent corneal erosions

• Patients with map-dot fingerprint and/or Fuch’s corneal dystrophies

• Corneal transplants

• Patients undergoing phototherapeutic keratectomy (PTK) for anterior stromal corneal dystrophies

Oral

TB4 plays a role in suppressing the production of interleukin-8 following stimulation by tumor necrosis factor-alpha, acting as an antimicrobial, anti-inflammatory and antiapoptotic factor on gingival fibroblasts.

Cardiac

Cardiac hypoxic heart disease is a predominant cause of disability and death worldwide. TB4 is the only known molecule to initiate organ wide activation of the embryonic coronary development program in adult mammalian hearts. TB4 has been reported effective when used to inhibit myocardial cell death, improve angiogenesis, have antifibrotic effects, decrease infarct size and activate endogenous cardiac progenitors. Treatment with TB4 is reported to reduce infarct volume and preserve cardiac function in preclinical models of cardiac ischemic injury.

CNS/Brain

As stated earlier, TB4 is widely distributed in a majority of mammalian tissues and cell types, including those of the CNS (central nervous system). It is expressed in most neural cell types of the developing brain and in a subset of neurons and microglia. TB4 is locally synthesized in neurons for the regulation of neurite outgrowth. It is also up-regulated in various pathological conditions such as focal ischemia, Alzheimer’s disease, Huntington’s disease, hippocampal denervation, and kainic acid induced seizure. Its presence in the nervous system likely plays a role in neuroprotection, synaptogenesis, axon growth, cell migration, and plastic changes. If brain changes are suspected due to autoimmunity, TB4 is a great therapeutic choice.

Sepsis

Sepsis is the dysregulated host response to an infection resulting in life-threatening organ damage. Thymosin-beta 4 is reported to improve mortality when administered intravenously to septic rats. TB4 decreases inflammatory mediators, lowers reactive oxygen species, up-regulates anti-oxidative enzymes, anti-inflammatory genes, and anti-apoptotic enzymes making it an interesting protein to study in sepsis.

Non-Alcoholic Fatty Liver Disease - NAFLD

Studies report that TB4 is negatively correlated with endotoxemia, and could suppress proinflammatory TLR signaling and reduce inflammatory cytokines. According to the gut-liver axis theory, the effects of TB4 could play an important role in the treatment of NAFLD.

Researchers detected TB4 expression in the sera and tissues of patients with chronic hepatitis B combined with NAFLD, and observed that the TB4 level was negatively correlated with inflammation and fibrosis scores, and TB4 expression in both serum and liver tissue was negatively correlated with TNF-a expression.

TB4 plays a defensive role in the development of liver disease by inhibiting oxidative stress and proinflammatory factors. When the concentration of serum TB4 was compared between patients with NAFLD and healthy controls, serum TB4 levels in patients with NAFLD were significantly lower. After treatment and subsequent improvement in liver function, the concentration of TB4 increased.

In addition, another set of researchers observed 83 cases of NAFLD and 80 healthy patients, and reported that TB4 level can effectively be used as a biomarker of liver function, as increased Bb4 level indicated improved liver function, and decreased TB4 level indicated severe liver damage. These studies indicate that TB4 expression is related to liver function in NAFLD patients.

 

Summary of beneficial effects of thymosin beta 4 (Tb4) include:

• Differentiation of endothelial cells (blood and lymphatic vessels)

• Growth of new blood vessels - angiogenesis

• Keratinocyte migration

• Improves collagen deposition

• Decreases scar tissue formation

• Overall improved tissue repair

• Faster healing of wounds

• Repair of tendons and ligaments

• Improved flexibility of joints

• Prevents the formations of adhesions and fibrous bands in muscles, tendons and ligaments

• Decreases inflammation in various tissue types

• Increased muscle growth

• Increased in endurance and strength

• Relaxed muscle spasm and improved muscle tone

• Repair damaged heart tissue following a heart attack

• Healing of ulcers and lesions (including pressure, venous, stomach and intestinal ulcers)

• Promotes hair growth

• Protects and restores neurons after brain injury

• Protects brain neurons from autoimmune inflammation

 

Summary

What is Thymosin Beta-4?

Thymosin is a hormone secreted from the thymus. The thymus is responsible for regulating the immune system and tissue repair. Thymosin Beta-4 has been found to play an important role in protection, regeneration, and remodeling of injured or damaged tissue. It is being researched for acute injuries, wound healing and surgical repair. It acts as a major actin-sequestering molecule and can be taken after cardiac injury for better healing of the tissue in the heart.

 

How does Thymosin Beta-4 work?

Thymosin Beta-4 is typically found in both types of muscle in the body – skeletal (the muscles that are required to move) and smooth (muscles such as those in the heart). When damage to tissue occurs, Thymosin Beta-4 is upregulated. Thymosin Beta-4 is released in the body to help people heal from traumas. In the process of healing from injury, it also acts to reduce the amount of scar tissue and improve flexibility. It also has potent anti-inflammatory properties.

According to research, TB4 has been shown to calm muscle spasms, improve muscle tone, increase exchange of substances between cells, encourage tissue repair, help maintain flexibility, and reduce inflammation of tissue in joints. In addition, this peptide encourages growth of new blood cells in tissue, increases endurance and strength, and prevents the formation of adhesions and fibrous bands in muscles, tendons, and ligaments.

 

References:

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Crockford D, Turjman N, Allan C, et al. Thymosin beta4: structure, function , and biological properties current and future clinical applications. Ann NY Acad Sci. 2010;1194:179-89.

Goldstein AL, Hannappei E, Sosne G, et al. Thymosin beta4: a multifunctional regenerative peptide: Basic properties and clinical applications. Expert Opin Biol Ther. 2012;12(1):37-51.

Huff T, Müller CS, Otto AM, Netzker R, Hannappel E. β-Thymosins, small acidic peptides with multiple functions. Int J Biochem Cell Biol. 2001;33(3):205–20

Jiang Y, Han T, Zhang Z, et al. Potential role of thymosin beta 4 in the treatment of nonalcoholic fatty liver disease. Chron Dis Trans Med. 2017;3:165-68.

Kleinman HK, Sosne G. Thymosin B4 promotes dermal healing. Vitam Horm. 2016;102:251-75.

Philp D, Huff T, Gho YS, et al. The actin binding site on thymosin beta4 promotes angiogenesis. FASEB J. 2003;17(14):2103-5.

Philip D, Kleinman HK, Animal studies with thymosin beta, a multifunctional tissue repair and regeneration peptide. Ann NY Acad Sci. 2010;1194:81-6.

Pipes GT, Yang J. Cardioprotection by thymosin beta4. Vitam Horm. 2016;102:209-26.

Sanders MC, Goldstein AL, Wang Y. Thymosin B4 (Fx peptide) is a potent regulator of actin polymerization in living cells. Proc Natl Acad Sci USA. 1992;89:4678-4682.

Shrivastava S, Srivastava D, Olson EN, et al. Thymosin beta4 and cardiac repair. Ann NY Acad Sci. 2010;1194:87-96.

Sosne G, Kleinman HK. Primary mechanisms of thymosin b4 repair activity in dry eye disorders and other tissue injuries. Inves Ophth Visual Sci. 2015;56(9).

Sun W, Lim H.Neurotrophic roles of the beta-thymosins in the development and regeneration of the nervous system. Ann. N.Y. Acad. Sci.. 2007;1112: 210–218.