Endothelial lineage differentiation from induced pluripotent stem cells is regulated by microRNA-21 and transforming growth factor β2 (TGF-β2) pathways.

Finding a suitable cell source for endothelial cells (ECs) for cardiovascular regeneration is a challenging issue for regenerative medicine. In this paper, we describe a novel mechanism regulating induced pluripotent stem cells (iPSC) differentiation into ECs, with a particular focus on miRNAs and their targets. We first established a protocol using collagen IV and VEGF to drive the functional differentiation of iPSCs into ECs and compared the miRNA signature of differentiated and undifferentiated cells. Among the miRNAs overrepresented in differentiated cells, we focused on microRNA-21 (miR-21) and studied its role in iPSC differentiation. Overexpression of miR-21 in predifferentiated iPSCs induced EC marker up-regulation and in vitro and in vivo capillary formation; accordingly, inhibition of miR-21 produced the opposite effects. Importantly, miR-21 overexpression increased TGF-2 mRNA and secreted protein level, consistent with the strong up-regulation of TGF-2 during iPSC differentiation. Indeed, treatment of iPSCs with TGF-2 induced EC marker expression and in vitro tube formation. Inhibition of SMAD3, a downstream effector of TGF-2, strongly decreased VE-cadherin expression. Furthermore,TGF-2 neutralization and knockdown inhibited miR-21-induced EC marker expression. Finally, we confirmed the PTEN/Akt pathway as a direct target of miR-21, and we showed that PTEN knockdown is required for miR-21-mediated endothelial differentiation. In conclusion, we elucidated a novel signaling pathway that promotes the differentiation of iPSC into functional ECs suitable for regenerative medicine applications

A Cytokine-Like Protein Dickkopf-Related Protein 3 Is Atheroprotective

This work was mainly supported by the British Heart Foundation (RG/14/6/31144), and partially by the Oak Foundation, National Natural Science Foundation of China (81370521, 81320157, and 81670400), The Importation and Development of High-Caliber Talents Project of Beijing Municipal Institutions (CIT&TCD20150325), The Key Science and Technology Project of Beijing Municipal Institutions (KZ201610025025), The Fok Ying-Tong Education Foundation (151041), and the Beijing Haiju Project. Drs Kiechl, Willeit, Mayr, and Weger were supported by the excellence initiative (Competence Centers for Excellent Technologies) of the Austrian Research Promotion Agency: Research Center of Excellence in Vascular Ageing, Tyrol (K-Project No. 843536) funded by the Wirtschaftsagentur Wien and Standortagentur Tirol

Controlled oxygen release from pyridone endoperoxides promotes cell survival under anoxic conditions

In tissue engineering, survival of larger constructs remains challenging due to limited supply with oxygen caused by a lack of early vascularization. Controlled release of oxygen from small organic molecules represents a possible strategy to prevent cell death under anoxic conditions. A comprehensive study of methylated pyridone-derived endoperoxides has led to the development of water-soluble molecules that undergo retro Diels-Alder reactions in aqueous environment releasing oxygen in high yield and with half-lives of up to 13 hours. These molecules in combination with vitamin C as singlet oxygen quencher significantly improved survival of 3T3 fibroblasts and rat smooth muscle cells challenged with oxygen-depleted conditions