Browsing by Author "Qian, Hong"

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    Competition between DNA Methylation, Nucleotide Synthesis, and Antioxidation in Cancer versus Normal Tissues
    (AACR, 2017-08) Cao, Sha; Zhu, Xiwen; Zhang, Chi; Qian, Hong; Schuttler, Heinz-Bernd; Gong, Jianping; Xu, Ying; Medical and Molecular Genetics, School of Medicine
    Global DNA hypomethylation occurs in many cancer types, but there is no explanation for its differential occurrence or possible impact on cancer cell physiology. Here we address these issues with a computational study of genome-scale DNA methylation in 16 cancer types. Specifically, we identified (i) a possible determinant for global DNA methylation in cancer cells and (ii) a relationship between levels of DNA methylation, nucleotide synthesis, and intracellular oxidative stress in cells. We developed a system of kinetic equations to capture the metabolic relations among DNA methylation, nucleotide synthesis, and antioxidative stress response, including their competitions for methyl and sulfur groups, based on known information about one-carbon metabolism and trans-sulfuration pathways. We observed a kinetic-based regulatory mechanism that controls reaction rates of the three competing processes when their shared resources are limited, particularly when the nucleotide synthesis rates or oxidative states are high. The combination of this regulatory mechanism and the need for rapid nucleotide synthesis, as well as high production of glutathione dictated by cancer-driving forces, led to the nearly universal observations of reduced global DNA methylation in cancer. Our model provides a natural explanation for differential global DNA methylation levels across cancer types and supports the observation that more malignant cancers tend to exhibit reduced DNA methylation levels. Insights obtained from this work provide useful information about the complexities of cancer due to interplays among competing, dynamic biological processes.
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    A Pulmonary Vascular Model From Endothelialized Whole Organ Scaffolds
    (Frontiers Media, 2021-11-19) Yuan, Yifan; Leiby, Katherine L.; Greaney, Allison M.; Brickman Raredon, Micha Sam; Qian, Hong; Schupp, Jonas C.; Engler, Alexander J.; Baevova, Pavlina; Adams, Taylor S.; Kural, Mehmet H.; Wang, Juan; Obata, Tomohiro; Yoder, Mervin C.; Kaminski, Naftali; Niklason, Laura E.; Pediatrics, School of Medicine
    The development of an in vitro system for the study of lung vascular disease is critical to understanding human pathologies. Conventional culture systems fail to fully recapitulate native microenvironmental conditions and are typically limited in their ability to represent human pathophysiology for the study of disease and drug mechanisms. Whole organ decellularization provides a means to developing a construct that recapitulates structural, mechanical, and biological features of a complete vascular structure. Here, we developed a culture protocol to improve endothelial cell coverage in whole lung scaffolds and used single-cell RNA-sequencing analysis to explore the impact of decellularized whole lung scaffolds on endothelial phenotypes and functions in a biomimetic bioreactor system. Intriguingly, we found that the phenotype and functional signals of primary pulmonary microvascular revert back-at least partially-toward native lung endothelium. Additionally, human induced pluripotent stem cell-derived endothelium cultured in decellularized lung systems start to gain various native human endothelial phenotypes. Vascular barrier function was partially restored, while small capillaries remained patent in endothelial cell-repopulated lungs. To evaluate the ability of the engineered endothelium to modulate permeability in response to exogenous stimuli, lipopolysaccharide (LPS) was introduced into repopulated lungs to simulate acute lung injury. After LPS treatment, proinflammatory signals were significantly increased and the vascular barrier was impaired. Taken together, these results demonstrate a novel platform that recapitulates some pulmonary microvascular functions and phenotypes at a whole organ level. This development may help pave the way for using the whole organ engineering approach to model vascular diseases.