Thymosin β4: potential to treat epidermolysis bullosa and other severe dermal injuries

Yang, Won Seok; Kang, Shinwook; Sung, Jihye; Kleinman, Hynda K.

doi:10.1684/ejd.2019.3642

Cited by 14 publications

(8 citation statements)

References 101 publications

(165 reference statements)

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“…In cardiomyocytes, TMSB4X function is required for proper sarcomere organization (Smart et al, 2017), and in the adult mouse epidermis, TMSB4X is a positive regulator of hair growth (Gao et al, 2015). The function of TMSB4X in the skin is particularly relevant to human health, and TMSB4X peptides are being tested in clinical trials for the treatment of dermal ulcers and epidermolysis bullosa, a group of skin-blistering diseases (Goldstein and Kleinman, 2015;Kleinman and Sosne, 2016;Yang et al, 2019). However, the functions and underlying molecular mechanisms of TMSB4X in epidermal development have not yet been investigated.…”

Section: Introductionmentioning

confidence: 99%

Thymosin β4 is essential for adherens junction stability and epidermal planar cell polarity

et al. 2020

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Planar cell polarity (PCP) is essential for tissue morphogenesis and homeostasis; however, the mechanisms that orchestrate the cell shape and packing dynamics required to establish PCP are poorly understood. Here, we identified a major role for the globular (G)-actin-binding protein thymosin-β4 (TMSB4X) in PCP establishment and cell adhesion in the developing epidermis. Depletion of Tmsb4x in mouse embryos hindered eyelid closure and hair-follicle angling owing to PCP defects. Tmsb4x depletion did not preclude epidermal cell adhesion in vivo or in vitro; however, it resulted in abnormal structural organization and stability of adherens junction (AJ) due to defects in filamentous (F)-actin and G-actin distribution. In cultured keratinocytes, TMSB4X depletion increased the perijunctional G/F-actin ratio and decreased G-actin incorporation into junctional actin networks, but it did not change the overall actin expression level or cellular F-actin content. A pharmacological treatment that increased the G/F-actin ratio and decreased actin polymerization mimicked the effects of Tmsb4x depletion on both AJs and PCP. Our results provide insights into the regulation of the actin pool and its involvement in AJ function and PCP establishment.

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Section: Introductionmentioning

confidence: 99%

Thymosin β4 is essential for adherens junction stability and epidermal planar cell polarity

et al. 2020

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“…Tβ4 was first isolated from the thymus and belongs to the β-thymosin family, which consists of several structurally related amino acid polypeptides ( 27 ). Tβ4 lacks a secretion signal, therefore it is speculated that its presence in body fluids might be due to damaged cell ( 10 , 27 , 28 ). Tβ4 was reported to take part in tissue damage-related diseases, such as dermal injuries, cerebral ischemia-reperfusion injury, heart injury and CLI ( 14 , 15 , 28 - 30 ).…”

Section: Discussionmentioning

confidence: 99%

“…Tβ4 lacks a secretion signal, therefore it is speculated that its presence in body fluids might be due to damaged cell ( 10 , 27 , 28 ). Tβ4 was reported to take part in tissue damage-related diseases, such as dermal injuries, cerebral ischemia-reperfusion injury, heart injury and CLI ( 14 , 15 , 28 - 30 ). Furthermore, during tissue injury, Tβ4 can promote endothelial cell migration and tube formation ( 10 , 12 ).…”

Section: Discussionmentioning

confidence: 99%

Thymosin‑β�4 induces angiogenesis in critical limb ischemia mice via regulating Notch/NF‑κB pathway

Cai

et al. 2020

Int J Mol Med

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Thymosin-β 4 (Tβ4) has been reported to exert a pro-angogenic effect on endothelial cells. However, little is known on the role and underlying mechanisms of Tβ4 on critical limb ischemia (cLI). The present study aimed therefore to investigate the mechanisms and pro-angiogenic effects of Tβ4 in cLI mice. Tβ4 overexpression lentiviral vector was first transfected into HUVEC and CLI mice model, and inhibitors of Notch pathway (dAPT) and NF-κB pathway (BMS) were also applied to HUVEC and CLI mice. Subsequently, MTT, tube formation and wound healing assays were used to determine the cell viability, angiogenesis and migratory ablity of HUVEC, respectively. Western blotting, reverse transcription, quantitative PCR, immunofluorescence and immunohistochemistry were used to detect the expression of the angiogenesis-related factors angiopoietin-2 (Ang2), TEK receptor tyrosine kinase 2 (tie2), vascular endothelial growth factor A (VEGFA), CD31 and α-smooth muscle actin (α-SMA) and the Notch/NF-κB pathways-related factors NOTcH1 intracellular domain (N1Icd), Notch receptor 3 (Notch3), NF-κB and p65 in HUVEC or CLI mice muscle tissues. The results demonstrated that Tβ4 not only enhanced the cell viability, angiogenesis and migratory ability of HUVEC but also promoted the expression of Ang2, tie2, VEGFA, N1ICD, Notch3, NF-κB, and phosphorylated (p)-p65 in HUVEC. In addition, Tβ4 promoted the expression of cd31, α-SMA Ang2, tie2, VEGFA, N1ICD and p-p65 in CLI mice muscle tissues. Treatment with dAPT and BMS had opposite effects of Tβ4, whereas Tβ4 reversed the effect of dAPT and BMS. The findings from the present study suggested that Tβ4 may promote angiogenesis in cLI mice via regulation of Notch/NF-κB pathways.

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“…Patients with pressure ulcers, stasis ulcers, and epidermolysis bullosa benefited from TB4 therapy. The results concluded TB4 is safe, well-tolerated and possessed additional use for skin regeneration [103,104].…”

Section: Thymosin Beta-4 Holds Significant Potential To Initiate Organ Regeneration and Repair By Influencing Multiple Senescence Relatedmentioning

confidence: 91%

Utilizing Developmentally Essential Secreted Peptides Such as Thymosin Beta-4 to Remind the Adult Organs of Their Embryonic State—New Directions in Anti-Aging Regenerative Therapies

Maar

Hetenyi

Maar

et al. 2021

Cells

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Our dream of defeating the processes of aging has occupied the curious and has challenged scientists globally for hundreds of years. The history is long, and sadly, the solution is still elusive. Our endeavors to reverse the magnitude of damaging cellular and molecular alterations resulted in only a few, yet significant advancements. Furthermore, as our lifespan increases, physicians are facing more mind-bending questions in their routine practice than ever before. Although the ultimate goal is to successfully treat the body as a whole, steps towards regenerating individual organs are even considered significant. As our initial approach to enhance the endogenous restorative capacity by delivering exogenous progenitor cells appears limited, we propose, utilizing small molecules critical during embryonic development may prove to be a powerful tool to increase regeneration and to reverse the processes associated with aging. In this review, we introduce Thymosin beta-4, a 43aa secreted peptide fulfilling our hopes and capable of numerous regenerative achievements via systemic administration in the heart. Observing the broad capacity of this small, secreted peptide, we believe it is not the only molecule which nature conceals to our benefit. Hence, the discovery and postnatal administration of developmentally relevant agents along with other approaches may result in reversing the aging process.

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Thymosin β4: potential to treat epidermolysis bullosa and other severe dermal injuries

Cited by 14 publications

References 101 publications

Thymosin β4 is essential for adherens junction stability and epidermal planar cell polarity

Thymosin β4 is essential for adherens junction stability and epidermal planar cell polarity

Thymosin‑β�4 induces angiogenesis in critical limb ischemia mice via regulating Notch/NF‑κB pathway

Utilizing Developmentally Essential Secreted Peptides Such as Thymosin Beta-4 to Remind the Adult Organs of Their Embryonic State—New Directions in Anti-Aging Regenerative Therapies

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