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Thymosin beta-4
Thymosin beta-4 is a small peptide with G actin-sequestering action. It is associated with induction of angiogenesis, accelerated wound healing, and increased metastatic potential of tumor cells. Thymosin beta-4 promotes angiogenesis, wound repair, and hair growth in normal and aged rodents [6]. It acts by increasing angiogenesis and cell migration and is currently in clinical trials for wound repair.
Thymosin beta-4 promotes myocardial and endothelial cell migration in the embryonic heart and retains this property in postnatal cardiomyocytes [7]. Survival of embryonic and postnatal cardiomyocytes in culture was also enhanced by thymosin beta-4. Thymosin beta-4 formed a functional complex with PINCH and integrin-linked kinase (ILK), resulting in activation of the survival kinase Akt (protein kinase B). After coronary artery ligation in mice, thymosin beta-4 treatment resulted in upregulation of ILK and Akt activity in the heart, enhanced early myocyte survival, and improved cardiac function. These findings suggest that thymosin beta-4 promotes cardiomyocyte migration, survival, and repair, and the pathway it regulates may be a new therapeutic target in the setting of acute myocardial damage.
Some NSAIDs induce thymosin beta-4 expression in a time- and concentration-dependent manner. Indometacin and SC-560 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole] induce thymosin beta-4 expression, whereas sulindac sulfide does not. Some NSAIDs induce actin cytoskeletal reorganization, a precursory step to many dynamic processes that regulate growth and motility, including tumorigenesis [8].
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1 Introduction
Thymosin beta 4 (Tβ4) is a highly conserved, naturally occurring, water-soluble regenerative peptide that is found in all tissues and in all cell types, except red blood cells (Goldstein, Hannappel, Sosne, & Kleinman, 2012; Goldstein & Kleinman, 2015). It is also found in the blood and in other body fluids, including tears, saliva, cerebrospinal fluid, and wound fluids (Badamchian et al., 2007; Huang, Wang, Barnes, & Elmets, 2006; Mohring, Kellmann, Jurgens, & Schrader, 2005). Both platelets and leukocytes release Tβ4 into the wound fluid such that the final concentration is 13 μg/mL (Fromm, Gunne, Bergman, et al., 1996; Hannappel & van Kampen, 1987).
Although Tβ4 contains only 43 amino acids, it appears to have a wide range of regenerative activities and specific sites on the molecule have been shown to mediate these effects (Goldstein & Kleinman, 2015; Sosne, Qiu, Goldstein, & Wheater, 2010). Both chemically synthesized and recombinant forms have shown efficacy for dermal healing in preclinical models and in human patients (Ehrlich & Hazard, 2012; Kim & Kwon, 2014, 2015; Malinda et al., 1999; Philp, Badamchian, et al., 2003; Philp & Kleinman, 2010; Philp et al., 2006; Ti et al., 2015; Treadwell et al., 2012). A dimeric form has been found to accelerate the rate of dermal healing in an animal model more rapidly than that of the parent molecule (Xu et al., 2013). Tβ4 has also shown repair and regenerative activity in a number of other injury models, such as traumatic brain injury, spinal cord injury, stroke, a model of multiple sclerosis, ischemic limbs, and cardiac damage due to ischemia (Bock-Marquette, Saxena, White, Dimaio, & Srivastava, 2004; Cheng, Kuang, Zhang, Ju, & Wang, 2014; Dube, Bollini, Smart, & Riley, 2012; Morris, Chopp, Zhang, Lu, & Zhang, 2010; Morris et al., 2014; Philp & Kleinman, 2010; Postrach et al., 2014; Smart et al., 2007; Sopko et al., 2011; Ti et al., 2015, Wang et al., 2012; Wei, Kim, Li, Wu, & Gupta, 2014; Xiong, Mahmood, Meng, et al., 2011; Zhang, Zhang, Morris, et al., 2009; Zuo et al., 2013). The processes and pathways for Tβ4-mediated repair are similar in these various tissues and support the observed promotion of dermal healing.
The first study to show that Tβ4-promoted tissue repair was a dermal study performed in rats (Malinda et al., 1999). It had previously been found to promote angiogenesis and was reported to be high in platelets (Grant et al., 1995; Hannappel & van Kampen, 1987; Malinda, Goldstein, & Kleinman, 1997; Philp, Huff, Gho, Hannappel, & Kleinman, 2003). Since platelets are the first cells to enter a wound, it was clear that Tβ4 should be tested in dermal wounds in an animal model (Malinda et al., 1997, 1999; Philp, Badamchian, et al., 2003). In the first dermal study using 8 mm full-thickness punch wounds in rats, Tβ4 at 5 μg/50 μL of phosphate-buffered saline was found to accelerate wound closure, increase angiogenesis, and accelerate collagen deposition (Malinda et al., 1999). Tβ4 was only applied at the time of injury and at 48 h since after that the crust had formed. Visible macroscopic improvement was seen in the treated group by day 4. The study also found that Tβ4 promoted keratinocyte migration in vitro with activity in the picogram range. The findings were confirmed in various additional animal models (Table 1) and led to the clinical trials for hard to heal wound in patients as detailed in Table 2.
Table 1. Animal Studies: Increased Dermal Healing
Model Dose Outcome Mechanism References Rat: skin flaps 5 mg/kg IP 2 ×/day 7 days Flap survival Increased VEGF Decreased SOD Increased malondialdehyde Lin, Lin, Lin, Huang, and Cao (2015) Mouse: burn 5.30 mg/kg Intradermal 2 ×/week 2 weeks Increased closure Healing Angiogenesis HSP70 Increased actin remodeling Kim and Kwon (2015) Mouse: burn Diabetic 5 mg/kg Intradermal 2 ×/week 2 weeks Increased closure Granulation Angiogenesis Decreased RAGE Kim and Kwon (2015) Rat: hind limb Ischemia diabetes Tβ4 in collagen/chitosan sponge 21 days Increased angiogenesis Healing Decreased TNF IL (inflammation) Increased VEGF PDGF (angiogenesis) Ti et al. (2015) Rat: punch wound Recombinant dimer at 0.5, 0.25, 0.125 mg/mL 2 ×/day 21 days Increased healing Angiogenesis Increased cell migration Xu et al. (2013) Mouse: punch wound Recombinant 5 μg/50 μL PBS days 0, 2 Increased healing Cell migration Li et al. (2007) Rat: punch wound 5 μg/50 μL topical days 0, 2 Increased healing Angiogenesis Cell migration Philp, Badamchian, et al. (2003) and Philp, Huff, et al. (2003) Rat: punch wound 60 μg IP days 0, 2 Improved healing Cell migration Malinda et al. (1999)
Table 2. Human Studies: Increased Trend in Rate of Dermal Healing
Wound Type Patients (#) Study Duration (Days) Optimal Dose (%)a Outcome Pressure ulcers (stages III and IV) 72 84 0.02 ⇑ Healing rate trendb,c Stasis ulcers 72 84 0.03 ⇑ Healing rate trendb,d Epidermolysis bullosa 28 56 0.03 ⇑ Healing rate trende,f,g
a Three doses and placebo were tested in all three phase 2 trials. Dose and frequency: 0. 0.01%, 0.02%, or 0.03% and 0.10% were given every day for the study duration. b Data are from Treadwell et al. (2012). c Mean healing rate 22 days vs 57 days for placebo, not statistically significant. d Mean healing rate 39 days vs 71 days for placebo, not statistically significant. e Data analyzed by diving wound size at postbaseline visit by mean wound size at baseline. f Unpublished. g Not statistically significant.
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Abstract
No agent has been identified that significantly accelerates the repair of chronic dermal wounds in humans. Thymosin beta 4 (Tβ4) is a small, abundant, naturally occurring regenerative protein that is found in body fluids and inside cells. It was found to have angiogenic and antiinflammatory activity and to be high in platelets that aggregate at the wound site. Thus we used Tβ4 initially in dermal healing. It has since been shown to have many activities important in tissue protection, repair, and regeneration. Tβ4 increases the rate of dermal healing in various preclinical animal models, including diabetic and aged animals, and is active for burns as well. Tβ4 also accelerated the rate of repair in phase 2 trials with patients having pressure ulcers, stasis ulcers, and epidermolysis bullosa wounds. It is safe and well tolerated and will likely have additional uses in the skin and in injured organs for tissue repair and regeneration.
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β-Thymosins 4 and 10 are thymus-derived small peptides involved in maintaining of a pool of monomeric actin in cells. They are very abundant in the adult rat brain (Gomez-Marquez et al., 1993). Carpintero et al. (1999a,b) have demonstrated that the β-thymosin 4, and to a lesser extent β-thymosin 10, are up-regulated at 3–4 h mainly in CA fields of the hippocampus.
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4.1.4 Thymosin Beta 4 X-linked (TMSB4X)
Thymosin Beta 4 X-linked (TMSB4X) is a protein that is involved in actin polymerisation. It is responsible for sequestration of actin. Other than that, it is also involved in processes like cell proliferation and differentiation. Interestingly, it was found that plasma protein expression of TMSB4X was elevated in PD patients (Yuan Zhao et al., 2022). Quantification of around 555 proteins was done using tandem mass spectroscopy. From that, around 25 proteins were modulated in case of PD patients. TMSB4X is one such gene that is actively involved in PD pathogenesis. Similarly, in another study it was found that TMSB4X was upregulated in MPTP induced PD mouse model (Guo et al., 2022). However, there are limited reports on this gene and hence, its role is ambiguous. Further studies can confirm and determine its definitive role in PD pathology.
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F THYMOSIN β4
Thymosin β4 is the first of the biologically active polypeptides from the β region of thymosin fraction 5 to be completely characterized (Low et al., 1981). Thymosin β4 was isolated by ion-exchange chromatography on a column of carboxymethyl-cellulose (CM-52) in 10 mM NaOAC, 1 mM 2-mercaptoethanol, pH 5.0. Two stepwise linear gradients of 0-0.5 M NaCl and 0.5-1.0 M NaCl were used for the elution. Thymosin β4 was derived from the second retained peak of the carboxymethyl-cellulose column. It was further purified by gel filtration on Sephadex G-50 in 6 M guanidinium–HCl. The third protein peak was pooled and desalted on a Sephadex G-10 column in sterile water. The purified sample so obtained is identified as thymosin β4. The complete sequence of β4 is shown in Fig. 3. Thymosin β4 is composed of 43 amino acid residues and has a molecular weight of 4982 and pI of 5.1. The N-terminal end of the peptide is blocked by an acetyl group.
This molecule induces TdT expression in TdT-negative murine bone marrow cells in vivo and in vitro. It also increases TdT activity in thymocytes from hydrocortisone immunosuppressed mice in vivo. Thus, it appears that thymosin β4 is acting on lymphoid stem cells and may influence the early stages of the maturation process of thymus-dependent lymphocytes.
A computer search for possible sequence homology between the sequence of thymosin β4 and other published protein sequences has been conducted (personal communication through the National Biomedical Research Foundation, Georgetown University Medical Center, Washington, D.C. 20007). The results do not indicate a statistically significant relationship of thymosin β4 to any other sequenced protein currently stored in the data bank. However, there is an interesting internal duplication between residues 18 to 30 and 31 to 43 as illustrated in Fig. 6.
FIG. 6. Regions of internal duplication of thymosin β4
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C Thymosin β4
Thymosin β4 has a molecular weight of 4982 and also has its N-terminal amino acid residue blocked by an acetyl group (Figure 17-6). It is the predominant thymosin in mammalian cells. This protein induces the expression of terminal deoxynucleotidyltransferase in transferase-negative mouse bone marrow cells in vitro and in vivo and increases the activity of this enzyme in hydrocortisone immune-suppressed mice in vivo. Thymosin β4 therefore acts on lymphoid stem cells and in the early maturation process of thymus-dependent lymphocytes.
The primary sequence of thymosin β4, like that of thymosin α1, does not show homology with the sequences of other known proteins. However, there is an internal sequence duplication. Although it would be attractive to consider thymosin β4 as a discrete hormone of the thymus, it appears in many tissues. No pro- or prepropeptide is formed as its precursor, and in mammalian tissues it is usually accompanied by a related peptide, thymosin β10. Thymosin β4 and β10 probably are not secretory peptide hormones.
Thymosin β3 is another peptide completely related to thymosin β4, but differs at the C-terminal end and has a molecular weight of 5500. It may also be a proteolytic fragment of thymosin β4. Thymosins β9, βmet 9, and β10, are minor variants of thymosin β4, and, like thymosin β4, they bind to ATP G actin. These proteins bind to monomeric actin and inhibit its polymerization. Part of the binding site of thymosin β9 has been shown to reside in the carboxy terminus. The N-terminal tetrapeptide of thymosin β4 is Ac-Ser-Asp-Lys-Pro and, by itself, affects cell cycle regulation by inhibiting in vivo entry of cell populations into the S phase; it also inhibits calmodulin-dependent phosphodiesterase. On the other hand, the 11-19 fragment of thymosin β4 (11-KFDKSKLKK-19) elevates phosphodiesterase activity even in the absence of Ca2+ or calmodulin. The N-terminal tetrapeptide of thymosin β4 Ac-SDKP, is formed from one-step enzymatic processing of thymosin β4, and both peptides have been detected in bone marrow cells. Incubation of [3H]thymosin β4 with intact or lysed bone marrow cells generated [3H]Ac-SDKP, and the tetrapeptide was not degraded further. Thus, Ac-SDKP appears to be a new regulator of the hemopoietic system.
The mRNA for thymosin β4 increases in fibroblasts induced to proliferate at the G1-S transition even in the presence of cycloheximide, but not in synchronized cycling cells. Thus, thymosin β4 is regulated by cell proliferation, but it is not a cell cycle-regulated gene.
Thymosin β4 synergizes with GM-CSF in myelopoiesis. There is a protein that binds thymosin β4, which is an elastase inhibitor. It is related to the serpin (serine protease inhibitor) family and plasminogen activator inhibitor 2. Thus, the physiological role of elastase inhibitors may be the thymosin β4-regulated rearrangement of leukocyte cytoskeleton components (see Figure 17.9).
FIGURE 17-9. Proposed mechanism of Tα1, and Tβ4 action. Tα1 activity has been associated with activation of cAMP/PKA- and PLC/PKC-dependent pathways. These second messenger pathways are typically G-protein receptor linked. Tα1 activity involves the production of prostaglandins and the activation of phospholipase A2 (PLA2). It is currently unknown whether the activation of PLA2 is directly through a receptor-mediated event or distal to the activation of PKC. The downstream targets of both PKC and PKA are transcription factors involved in cellular activation. The production of arachidonic acid metabolites have also been found to have significant effects on immune cell function. Although a large body of evidence has defined Tβ4 as a major intracellular actin sequestering protein, exogenous Tβ4 action has also been associated with the activation of tyrosine phosphorylation and increases in cytosolic calcium increases with subsequent alterations in cellular actin content(courtesy of Dr. Allan Goldstein, George Washington University, 1996).
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Abstract
Treatment with thymosin beta 4 (Tβ4) reduces infarct volume and preserves cardiac function in preclinical models of cardiac ischemic injury. These effects stem in part from decreased infarct size, but additional benefits are likely due to specific antifibrotic and proangiogenic activities. Injected or transgenic Tβ4 increase blood vessel growth in large and small animal models, consistent with Tβ4 converting hibernating myocardium to an actively contractile state following ischemia. Tβ4 and its degradation products have antifibrotic effects in in vitro assays and in animal models of fibrosis not related to cardiac injury. This large number of pleiotropic effects results from Tβ4’s many interactions with cellular signaling pathways, particularly indirect regulation of cellular motility and movement via the SRF–MRTF–G-actin transcriptional pathway. Variation in effects and effect sizes in animal models may potentially be due to variable distribution of Tβ4. Preclinical studies of PK/PD relationships and a reliable pharmacodynamic biomarker would facilitate clinical development of Tβ4.
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TBY4
Thymosin beta 4, Y-linked, TB4Y, encodes a minor histocompatibility antigen in its 5′-untranslated region that is a key activator of natural killer cells [53,54]. TB4Y may also have tumor suppressor properties and loss of TB4Y may contribute to male breast cancer [55]. The role of TB4Y in fertility is unknown.
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Thymosin
Thymosin is a 5-Da polypeptide hormone secreted by the thymus gland. Thymosin α1 stimulates the development of precursor T cells in the thymus to mature T cells. Of the thymosin peptide family, thymosin β4, is the most abundant member and is also expressed in many cell types. Thymosin β4 is the principal G-actin sequestering molecule in mammalian cells, playing an important role in the organization of the cytoskeleton. The structures of thymosins and the complex between thymosin β4 and actin are shown in Fig. 21.27.
Figure 21.27. (A) Structure of one of the thymosin family members, thymosin β9. (B) Complex of thymosin β4 (red) and actin (gray) monomer. (C) Molecular contact sites between actin and thymosin β4 (dark green). Image on the left is a “front” view and image on the right is back view.(A) Reproduced from Stoll, I.R., Voelter, W., Holak, T.A., 1979. Conformation of thymosin b9 in water/Fluoroalcohol solution determined by NMR spectroscopy. Biopolymers 41, 673; (B and C) Reproduced from Dos Remedios, C.G., et al., 2003. Actin binding proteins: regulation of cytoskeletal microfilaments. Physiol. Rev. 83: 433–473.
The activities of thymosin β4 are many and include promotion of cell migration, blood vessel formation, survival of cells, differentiation of stem cells, modulation of cytokines, chemokines, and certain proteases as well as upregulation of matrix molecules and gene expression. Thymosin β4 is being used in clinical applications. One example is its use in treating patients with ST-elevation myocardial infarction in combination with other methods of treatment.
Notably, thymosin β4 is secreted from platelets and aids in the formation of cross-links with fibrin in a time- and calcium-dependent manner in the process of clot formation. This cross-linking is mediated by factor XIIIa, a transglutaminase that is released with thymosin β4 from stimulated platelets. In this way, thymosin β4 stabilizes the blood clot (Fig. 21.28).
Figure 21.28. Thymosin β4 is coreleased from activated platelets together with factor XIIIa (transglutaminase) to form cross-links with fibrin during clot formation.Redrawn from http://www.fasebj.org/content/vol16/issue7/images/large/380421351s01.jpeg.
The maturation of the T cell from the bone marrow to the thymus to the peripheral blood, lymph nodes, spleen, and skin is pictured in Fig. 21.29.
Figure 21.29. Sequential expression of selected antigens during T-cell development. Depicted is the pathway of T-cell differentiation from the bone marrow stem cell to thymocyte maturation in the thymus, leading to the diversion of the CD4+ helper and CD8 cytotoxic suppressor cell sublineages, each of which undergoes further differentiation in peripheral lymphoid tissues. Certain disorders are shown under the associated phenotypes. Dr, HLA class II; T-ALL, T-cell acute lymphoblastic leukemia; TdT, terminal deoxynucleotidyl transferase.Reproduced from http://what-when-how.com/wp-content/uploads/2012/04/tmpDC36.jpg.
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