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Summary GATA2 is essential for the endothelial-to-hematopoietic transition (EHT) and generation of hematopoietic stem cells (HSCs). It is poorly understood how GATA2 controls the development of human pluripotent stem cell (hPSC)-derived HS-like cells. Here, using human embryonic stem cells (hESCs) in which GATA2 overexpression was induced by doxycycline (Dox), we elucidated the dual functions of GATA2 in definitive hematopoiesis before and after the emergence of CD34 + CD45 + CD90 + CD38 – HS-like cells. Specifically, GATA2 promoted expansion of hemogenic precursors via the EHT and then helped to maintain HS-like cells in a quiescent state by regulating cell cycle. RNA sequencing showed that hPSC-derived HS-like cells were very similar to human fetal liver-derived HSCs. Our findings will help to elucidate the mechanism that controls the early stages of human definitive hematopoiesis and may help to develop a strategy to generate hPSC-derived HSCs.

In this paper, a kind of morphing skin embedded with pneumatic muscle fibers is proposed from the bionics perspective. The elastic modulus of the designed pneumatic muscle fibers is experimentally determined and their output force is tested with internal air pressure varying from 0 to 0.4 MPa. The experimental results show that the contraction ratio of the pneumatic muscle fibers using the given material could reach up to 26.8%. Isothermal tensile tests are conducted on the fabricated morphing skin, and the results are compared with theoretical predictions based on the rule of mixture. When the strain is lower than 3% and in its linear-elastic range, the rule of mixture is proved to possess satisfying accuracy in the prediction of the elastic modulus of the morphing skin. Subsequently, the output force of the morphing skin is tested. It is revealed that when the volume ratio of the pneumatic muscle fibers is 0.228, the contraction ratio can reach up to 17.8%, which is satisfactory for meeting the camber requirement of morphing skin with maximum strain level below 2%. Finally, stress-bearing capability tests of the morphing skin on local uniformly distributed loads are conducted, and the test results show that the transverse stiffness of the morphing skin can be regulated by changing the internal air pressure. Under a uniformly distributed load of 540 Pa, the designed morphing skin is capable of varying by more than two orders of magnitude in the transverse stiffness by changing the internal air pressure.

Abdominal aortic aneurysm (AAA) is accepted as a chronic vascular inflammatory disease. However, how the inflammatory response is regulated during AAA formation is not fully understood. This study was undertaken to determine whether the long noncoding RNA (lncRNA) H19 (H19) promotes AAA formation by enhancing aortic inflammation. qRT-PCR detected the upregulation of H19 in human and mouse AAA tissue samples. Co-staining for H19 and the macrophage marker MAC-2 showed that H19 was located in vascular smooth muscle cells (VSMCs) and infiltrating aortic macrophages. In vivo overexpression of H19 increased vascular inflammation and induced AAA formation, which was supported by exacerbated aortic morphology, maximum aortic diameter values, elastin degradation, expression of interleukin-6 (IL-6) and macrophage chemoattractant protein-1 (MCP-1), and macrophage infiltration. H19 suppression resulted in the opposite effects. A rescue experiment indicated that IL-6 neutralization significantly mitigated the aortic inflammation and AAA formation evoked by H19 overexpression. Luciferase reporter assays and ex vivo experiments using VSMCs and macrophages confirmed that H19 induced aneurysm formation in part via endogenous competition with the let-7a microRNA to induce the transcription of its target gene, IL-6. This mechanism was further validated by in vivo experiments using a mutant H19 that could not effectively bind let-7a. Collectively, our study revealed a pathogenic H19/let-7a/IL-6 inflammatory pathway in AAA formation, which offers a new potential therapeutic strategy for AAA.

The work describes the design, manufacturing, and parametric modeling of a curved cellular structure (SILICOMB) with zero Poisson’s ratio produced using Kirigami techniques from polyetheretherketone films. The large deformation behavior of the cellular structure is evaluated using full-scale finite element methods and experimental tests performed on the cellular samples. Good agreement is observed between the mechanical behavior predicted by the finite element modeling and the three-point bending compression tests. Finite element simulations have also been used to perform a parametric analysis of the stiffness against the geometry of the cellular structures, showing a high degree of tailoring that these cellular structures could offer in terms of minimum relative density and maximum stiffness. The experimental results also show high levels of strain-dependent loss factors and low residual deformations after cyclic large deformation loading.

Antagonism of ROS signaling can inhibit cell apoptosis and autophagy, thus favoring the maintenance and expansion of hematopoietic stem cells. Alpha lipoic acid (ALA), a small antioxidant molecule, affects cell apoptosis by lowering the ROS level. In this study, we show that ALA promoted production of human pluripotent stem cells (hPSCs) derived hemogenic endothelial cells and hematopoietic stem/progenitor cells in vitro. Transcriptome analysis of hPSCs derived hemogenic endothelial cells showed that ALA promoted endothelial-to-hematopoietic transition by up-regulating RUNX1, GFI1, GFI1B, MEIS2, and HIF1A and down-regulating SOX17, TGFB1, TGFB2, TGFB3, TGFBR1, and TGFBR2. ALA also up-regulated sensor genes of ROS signals, including HIF1A, FOXO1, FOXO3, ATM, PETEN, SIRT1, and SIRT3, during the process of hPSCs derived hemogenic endothelial cells generation. However, in more mature hPSC-derived hematopoietic stem/progenitor cells, ALA reduced ROS levels and inhibited apoptosis. In particular, ALA enhanced development of hPSCs derived hematopoietic stem/progenitor cells by up-regulating HIF1A in response to a hypoxic environment. Furthermore, addition of ALA in ex vivo culture greatly improved the maintenance of functional cord blood HSCs by in vivo transplantation assay. Our findings support the conjecture that ALA plays an important role in efficient regeneration of hematopoietic stem/progenitor cells from hPSCs and maintenance of functional HSCs, providing insight into understanding of regeneration of early hematopoiesis for engineering clinically useful hPSCs derived hematopoietic stem/progenitor cells transplantation. Thus, ALA can be used in the study of hPSCs derived HSCs. K E Y W O R D S alpha lipoic acid, endothelial-to-hematopoietic transition (EHT), hematopoiesis, hematopoietic stem/progenitor cells, human pluripotent stem cells (hPSCs), ROS Abbreviations: AGM-S3, aorta-gonad-mesonephros (AGM)-S3 cells; ALA, alpha lipoic acid; hESCs, human embryonic stem cells; hPSCs, human pluripotent stem cells; HSCs, hematopoietic stem cells; ROS, reactive oxygen species. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.