Thymosin beta-4 improves endothelial function and reparative potency of diabetic endothelial cells differentiated from patient induced pluripotent stem cells

Su, Liping; Kong, Xu; Loo, Szejie; Gao, Yu; Liu, Bingli; Su, Xiaofei; Dalan, Rinkoo; Ma, Jianhua; Ye, Lei

doi:10.1186/s13287-021-02687-x

Cited by 10 publications

(7 citation statements)

References 44 publications

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“…To determine whether the effect of AA on inducing MLC2v expression and promoting ventricular-like hiPSC-CMs is limited on PCBC-CMs, AA was applied to a disease hiPSC line. DP3-hiPSC is a disease hiPSC line which was reprogrammed from dermal fibroblasts of patients with type 2 diabetes 28 , 29 . Similar to the results with PCBC-CM, AA significantly increased MLC2v protein expression in DP3-CMs Figure S5 .…”

Section: Resultsmentioning

confidence: 99%

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Ascorbic acid induces MLC2v protein expression and promotes ventricular-like cardiomyocyte subtype in human induced pluripotent stem cells derived cardiomyocytes

Gao¹,

Su²,

Wei³

et al. 2023

Theranostics

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Introduction: The potentially unlimited number of cardiomyocyte (CMs) derived from human induced pluripotent stem cells (hiPSCs) in vitro facilitates high throughput applications like cell transplantation for myocardial repair, disease modelling, and cardiotoxicity testing during drug development. Despite promising progress in these areas, a major disadvantage that limits the use of hiPSC derived CMs (hiPSC-CMs) is their immaturity. Methods : Three hiPSC lines (PCBC-hiPSC, DP3-hiPSCs, and MLC2v-mEGFP hiPSC) were differentiated into CMs (PCBC-CMs, DP3-CMs, and MLC2v-CMs, respectively) with or without retinoic acid (RA). hiPSC-CMs were either maintained up to day 30 of contraction (D30C), or D60C, or purified using lactate acid and used for experiments. Purified hiPSC-CMs were cultured in basal maturation medium (BMM) or BMM supplemented with ascorbic acid (AA) for 14 days. The AA treated and non-treated hiPSC-CMs were characterized for sarcomeric proteins (MLC2v, TNNI3, and MYH7), ion channel proteins (Kir2.1, Nav1.5, Cav1.2, SERCA2a, and RyR), mitochondrial membrane potential, metabolomics, and action potential. Bobcat339, a selective and potent inhibitor of DNA demethylation, was used to determine whether AA promoted hiPSC-CM maturation through modulating DNA demethylation. Results: AA significantly increased MLC2v expression in PCBC-CMs, DP3-CMs, MLC2v-CMs, and RA induced atrial-like PCBC-CMs. AA treatment significantly increased mitochondrial mass, membrane potential, and amino acid and fatty acid metabolism in PCBC-CMs. Patch clamp studies showed that AA treatment induced PCBC-CMs and DP3-CMs adaptation to a ventricular-like phenotype. Bobcat339 inhibited MLC2v protein expression in AA treated PCBC-CMs and DP3-CMs. DNA demethylation inhibition was also associated with reduced TET1 and TET2 protein expressions and reduced accumulation of the oxidative product, 5 hmC, in both PCBC-CMs and DP3-CMs, in the presence of AA. Conclusions: Ascorbic acid induced MLC2v protein expression and promoted ventricular-like CM subtype in hiPSC-CMs. The effect of AA on hiPSC-CM was attenuated with inhibition of TET1/TET2 mediated DNA demethylation.

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Section: Resultsmentioning

confidence: 99%

“…To determine mitochondrial membrane potential, mitochondrial staining was performed as described previously 28 , 29 . Briefly, hiPSC-CMs were cultured in 12-well plates and stained with mitochondria staining buffer using a Mitochondria Staining Kit (CS0390-1KT, Sigma, USA) for 30 min.…”

Section: Methodsmentioning

confidence: 99%

Ascorbic acid induces MLC2v protein expression and promotes ventricular-like cardiomyocyte subtype in human induced pluripotent stem cells derived cardiomyocytes

Gao¹,

Su²,

Wei³

et al. 2023

Theranostics

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“…Human iPSCs represent an unlimited source of cells for replacing damaged tissues. They can be successfully differentiated into different subtypes of vascular cells, such as ECs ( 19 , 20 ) and smooth muscle cells (SMCs) ( 21 , 22 ). In this study, we used an efficient method for differentiating hiPSCs to CD31 + CD144 + ECs as a source of EVs ( Figure 1A ).…”

Section: Resultsmentioning

confidence: 99%

Extracellular vesicles produced by human-induced pluripotent stem cell-derived endothelial cells can prevent arterial stenosis in mice via autophagy regulation

Feng

et al. 2022

Front. Cardiovasc. Med.

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Intravascular transplantation of human-induced pluripotent stem cells (hiPSCs) demonstrated a significant therapeutic effect in the treatment of restenosis by the paracrine function of extracellular vesicles (EVs). However, the risk of tumorigenicity and poor cell survival limits its clinical applications. In this study, we for the first time applied a highly efficient and robust three-dimensional (3D) protocol for hiPSC differentiation into endothelial cells (ECs) with subsequent isolation of EVs from the derived hiPSC-EC (ECs differentiated from hiPSCs), and validated their therapeutic effect in intimal hyperplasia (IH) models. We found that intravenously (iv) injected EVs could accumulate on the carotid artery endothelium and significantly alleviate the intimal thickening induced by the carotid artery ligation. To elucidate the mechanism of this endothelial protection, we performed miRNA expression profiling and found out that among the most conserved endothelial miRNAs, miR-126 was the most abundant in hiPSC-EC-produced EVs (hiPSC-EC-EV). MiR-126 depletion from hiPSC-EC-EV can hinder its protective effect on human umbilical vein endothelial cells (HUVECs) in an inflammatory process. A variety of functional in vitro studies revealed that miR-126 was able to prevent endothelial apoptosis after inflammatory stimulation, as well as promote EC migration and tube formation through autophagy upregulation. The latter was supported by in vivo studies demonstrating that treatment with hiPSC-EC-EV can upregulate autophagy in mouse carotid artery ECs, thereby preventing IH and modulating vascular homeostasis via remodeling of the vascular intima. Our findings suggest a regulatory mechanism for the therapeutic effect on arterial restenosis by autophagy regulation, and provide a potential strategy for clinical treatment of the disease.

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“…This dose of Tβ4 was based on previously published articles (37,38). Furthermore, similar doses were used by other investigators in experiments with HUVECs and hiPSC-ECs (40,41). The dose did not show any toxic effect or damage to the cells.…”

Section: Methodsmentioning

confidence: 99%

Effect of thymosin β4 on lipopolysaccharide‑stimulated brain microvascular endothelial cell remodeling: A possible role in blood‑brain barrier injury

Stewart,

Hejl,

Guleria

et al. 2023

Exp Ther Med

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War veterans, in particular, are more prone to mental illness as they are more likely to have encountered multiple traumatic brain injuries (TBIs) whilst serving on active duty in war zone areas. A TBI is known to cause mortality or serious neurological disabilities among survivors and elicits a number of pathological processes, including neuroinflammation and blood brain barrier (BBB) disruption, leading to secondary brain damage and subsequent impairment of the neurovascular unit. Although several drugs exhibit promising effects for TBI, the repertoire of currently available therapeutic strategies remains limited. Thymosin 4 (Tβ4) is a 43-amino acid G-acting sequestering peptide that confers neuroprotective potential in TBI models. However, its role in BBB function remains unclear. Further research into the mechanism of BBB disruption induced by TBI and its specific role in neurovascular pathophysiology is necessary. In the present study, the protective effects of Tβ4 in lipopolysaccharide (LPS)-stimulated gene expression of several tight junction proteins, inflammatory genes, apoptotic genes, and adhesion genes in human brain microvascular endothelial cells (hBMVECs), one of the pivotal cell types in the BBB, were reported. The results suggested that pretreatment with Tβ4 reversed the LPS-induced damage of BBB components in hBMVECs. Furthermore, these results identified neuregulin 1 as a possible target for Tβ4. Therefore, it is proposed that Tβ4-mediated cellular signaling in hBMVEC may be vital for understanding the association between the BBB and TBI pathophysiology, which warrants further investigation.

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Thymosin beta-4 improves endothelial function and reparative potency of diabetic endothelial cells differentiated from patient induced pluripotent stem cells

Cited by 10 publications

References 44 publications

Ascorbic acid induces MLC2v protein expression and promotes ventricular-like cardiomyocyte subtype in human induced pluripotent stem cells derived cardiomyocytes

Ascorbic acid induces MLC2v protein expression and promotes ventricular-like cardiomyocyte subtype in human induced pluripotent stem cells derived cardiomyocytes

Extracellular vesicles produced by human-induced pluripotent stem cell-derived endothelial cells can prevent arterial stenosis in mice via autophagy regulation

Effect of thymosin β4 on lipopolysaccharide‑stimulated brain microvascular endothelial cell remodeling: A possible role in blood‑brain barrier injury

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