Autologous vein grafts remain the only surgical alternative for many types of vascular reconstruction, but the failure rate of these grafts after 1 year approaches 20%.
The generation of induced pluripotent stem (iPS) cells is an important tool for regenerative medicine. However, the main restriction is the risk of tumor development. In this study we found that during the early stages of somatic cell reprogramming toward a pluripotent state, specific gene expression patterns are altered. Therefore, we developed a method to generate partial-iPS (PiPS) cells by transferring four reprogramming factors (OCT4, SOX2, KLF4, and c-MYC) to human fibroblasts for 4 d. PiPS cells did not form tumors in vivo and clearly displayed the potential to differentiate into endothelial cells (ECs) in response to defined media and culture conditions. To clarify the mechanism of PiPS cell differentiation into ECs, SET translocation (myeloid leukemia-associated) (SET) similar protein (SETSIP) was indentified to be induced during somatic cell reprogramming. Importantly, when PiPS cells were treated with VEGF, SETSIP was translocated to the cell nucleus, directly bound to the VE-cadherin promoter, increasing vascular endothelialcadherin (VE-cadherin) expression levels and EC differentiation. Functionally, PiPS-ECs improved neovascularization and blood flow recovery in a hindlimb ischemic model. Furthermore, PiPS-ECs displayed good attachment, stabilization, patency, and typical vascular structure when seeded on decellularized vessel scaffolds. These findings indicate that reprogramming of fibroblasts into ECs via SETSIP and VEGF has a potential clinical application.shear stress | stem cell therapy | vascular tissue engineering
The Lower Yangtze river belt is one of the most important metallogenic belts in China. The mechanisms responsible for ore genesis and the formation of related Cretaceous igneous rocks, such as adakite, A-type granitoid, and Nb-enriched basalt, remain controversial. Mesozoic granitoids in the Lower Yangtze river belt were mostly formed in the Early Cretaceous (140-125 Ma), and three granitoid belts-the inner, the south, and the north-have been defined according to petrological and geochemical characteristics. Previously, based mainly on negative εNd and high initial Sr isotope values, the adakitic rocks were generally attributed to partial melting of thickened or delaminated lower crust, both of which require crustal thickening. Mesozoic crustal thickening, however, is not supported by the development of extensional basins in the region. From the Late Jurassic to Cretaceous, eastern China was closely associated with subduction of the Pacific plate in the south and the Izanagi plate in the north. The midocean ridge (MOR) between these two plates was drifting toward and likely subducting under the Lower Yangtze river belt. A ridge subduction model can therefore explain the distribution of different magmatic rocks and ore deposits in the belt. Partial melting of subducting young, hot oceanic slabs close to the ridge formed adakitic rocks. The negative εNd values of adakitic rocks can be plausibly interpreted by mixing between adakitic magmas and enriched components in the lithospheric mantle, and/or crustal materials through AFC process. A slab window opened during ridge subduction as indicated by A-type granitoids in the center of the inner belt. Nb-enriched basalt found in the belt was likely formed by partial melting of a mantle wedge metasomatized by fluids released from the subducting slab at shallow depths.
Reendothelialization involves endothelial progenitor cell (EPC) homing, proliferation, and differentiation, which may be influenced by fluid shear stress and local flow pattern. This study aims to elucidate the role of laminar flow on embryonic stem (ES) cell differentiation and the underlying mechanism. We demonstrated that laminar flow enhanced ES cell–derived progenitor cell proliferation and differentiation into endothelial cells (ECs). Laminar flow stabilized and activated histone deacetylase 3 (HDAC3) through the Flk-1–PI3K–Akt pathway, which in turn deacetylated p53, leading to p21 activation. A similar signal pathway was detected in vascular endothelial growth factor–induced EC differentiation. HDAC3 and p21 were detected in blood vessels during embryogenesis. Local transfer of ES cell–derived EPC incorporated into injured femoral artery and reduced neointima formation in a mouse model. These data suggest that shear stress is a key regulator for stem cell differentiation into EC, especially in EPC differentiation, which can be used for vascular repair, and that the Flk-1–PI3K–Akt–HDAC3–p53–p21 pathway is crucial in such a process.
X-box binding protein 1 (XBP1) is a key signal transducer in endoplasmic reticulum stress response, and its potential role in the atherosclerosis development is unknown. This study aims to explore the impact of XBP1 on maintaining endothelial integrity related to atherosclerosis and to delineate the underlying mechanism. We found that XBP1 was highly expressed at branch points and areas of atherosclerotic lesions in the arteries of ApoE ؊/؊ mice, which was related to the severity of lesion development. In vitro study using human umbilical vein endothelial cells (HUVECs) indicated that disturbed flow increased the activation of XBP1 expression and splicing. Overexpression of spliced XBP1 induced apoptosis of HUVECs and endothelial loss from blood vessels during ex vivo cultures because of caspase activation and down-regulation of VE-cadherin resulting from transcriptional suppression and matrix metalloproteinase-mediated degradation. Reconstitution of VEcadherin by Ad-VEcad significantly increased Ad-XBP1s-infected HUVEC survival. Importantly, Ad-XBP1s gene transfer to the vessel wall of ApoE ؊/؊ mice resulted in development of atherosclerotic lesions after aorta isografting. These results indicate that XBP1 plays an important role in maintaining endothelial integrity and atherosclerosis development, which provides a potential therapeutic target to intervene in atherosclerosis.caspase ͉ endothelial integrity ͉ Ve-cadherin ͉ vessel graft ͉ mouse model A therosclerosis is a leading cause of death worldwide (1, 2).Accumulating evidence suggests that atherosclerosis is a multifactorial disease that can be initiated by risk factors (3-6). An important feature of atherosclerosis is its geographic distribution along the artery wall, i.e., occurring more frequently at curved or branching points in the vasculature, indicating that the flow pattern exerts an important role in the development of atherosclerotic lesions (7,8).Endothelial cells (ECs) are key cellular components of blood vessels, functioning as selectively permeable barriers between blood and tissues. It is believed that risk factors induce EC apoptosis, leading to the denudation or dysfunction of the intact endothelial monolayer, which causes lipid accumulation, monocyte adhesion, and inflammatory reactions that initiate atherosclerotic lesion (5, 9-12). Although information on risk factorinduced atherosclerosis has been accumulating, the underlying mechanism remains unclear.The X-box binding protein 1 (XBP1) was originally identified as a bZIP protein capable of binding to the cis-acting X box present in the promoter regions of human major histocompatibility complex class II genes (13) and is known to be essential for liver growth and B lymphocyte differentiation (14,15). In mammalian cells, XBP1 is a key signal transducer in the endoplasmic reticulum (ER) stress response. It has also been reported that there is a link between XBP1 and human disease (16,17). Although ER stress is reported to be involved in atherosclerosis (18)(19)(20)(21)(22), the role of XB...
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