Abstract
BackgroundPrior studies show that signature phenotypes of diabetic human induced pluripotent stem cells derived endothelial cells (dia-hiPSC-ECs) are disrupted glycine homeostasis, increased senescence, impaired mitochondrial function and angiogenic potential as compared with healthy hiPSC-ECs. In the current study, we aimed to assess the role of thymosin β-4 (Tb-4) on endothelial function using dia-hiPSC-ECs as disease model of endothelial dysfunction.Methods and resultsUsing dia-hiPSC-ECs as models of endothelial dysfunction, we determined the effect of Tb-4 on cell proliferation, senescence, cyto-protection, protein expression of intercellular adhesion molecule-1 (ICAM-1), secretion of endothelin-1 and MMP-1, mitochondrial membrane potential, and cyto-protection in vitro and angiogenic potential for treatment of ischemic limb disease in a mouse model of type 2 diabetes mellitus (T2DM) in vivo. We found that 600 ng/mL Tb4 significantly up-regulated AKT activity and Bcl-XL protein expression, enhanced dia-hiPSC-EC viability and proliferation, limited senescence, reduced endothelin-1 and MMP-1 secretion, and improved reparative potency of dia-hiPSC-ECs for treatment of ischemic limb disease in mice with T2DM. However, Tb4 had no effect on improving mitochondrial membrane potential and glycine homeostasis and reducing intercellular adhesion molecule-1 protein expression in dia-hiPSC-ECs.ConclusionsTb-4 improves endothelial dysfunction through enhancing hiPSC-EC viability, reducing senescence and endothelin-1 production, and improves angiogenic potency in diabetes.
Highlights
Vascular endothelial cells (ECs) play an important role in maintaining cardiovascular homeostasis throughSu et al Stem Cell Research & Therapy (2022) 13:13 disrupted glycine homeostasis, reduced cell proliferation, increased senescence, and impaired mitochondrial function and angiogenesis
The differentiated human induced pluripotent stem cells (hiPSCs)-ECs positive for CD31 expression and for both CD31 and CD144 expression were collected by fluorescence activated cell sorting (FACS) and expanded. hiPSC-ECs were cultured in EGM2-MV medium (Lonza, Switzerland) supplemented with B27, vascular endothelial growth factor-165 (VEGF), and SB-431542 (SB) [25, 26]
Tb4 (600 ng/mL) does not reduce ICAM‐1 protein expression and improve mitochondrial serine hydroxymethyltransferase (mSHMT) protein expression and mitochondrial membrane potential in dia‐hiPSC‐ECs We found that intercellular adhesion molecule-1 (ICAM-1) protein expression significantly up-regulated and mitochondrial membrane potential significantly reduced in DP2-ECs and DP3-ECs in a previous study [12]
Summary
Su et al Stem Cell Research & Therapy (2022) 13:13 disrupted glycine homeostasis, reduced cell proliferation, increased senescence, and impaired mitochondrial function and angiogenesis. Thymosin β4, a 5 kDa polypeptide, is composed of 43 amino acids [13] It is the most abundant member of the β-thymosin family in mammalian tissue and is regarded as the main G-actin sequestering peptide [13]. Prior studies show that signature phenotypes of diabetic human induced pluripotent stem cells derived endothelial cells (dia-hiPSC-ECs) are disrupted glycine homeostasis, increased senescence, impaired mitochondrial function and angiogenic potential as compared with healthy hiPSC-ECs. In the current study, we aimed to assess the role of thymosin β-4 (Tb-4) on endothelial function using dia-hiPSC-ECs as disease model of endothelial dysfunction
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