A multiscale in silico model of endothelial to mesenchymal transformation in a tumor microenvironment

Chowkwale, Mukti; Mahler, Gretchen J.; Huang, Pong-Yu; Murray, Bruce T.

doi:10.1016/j.jtbi.2019.08.012

Cited by 11 publications

(7 citation statements)

References 78 publications

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“…The PECAM-1 protein level in the subcellular model is utilized to trigger the transition from the qVEC to the activated valvular endothelial cell (aVEC) state, where the threshold for activation of VECs is set to half of the initial PECAM-1 level. Furthermore, aVECs can return to the quiescent state if the PECAM-1 level falls below the threshold, except in the case of a prolonged activity of the aVEC defined by a continuous active time period exceeding 48 hours (Chowkwale et al, 2019).…”

Section: Calcification Modelmentioning

confidence: 99%

“…In the CPM, the absolute values of the contact energies are not as important as the hierarchy of contact energies between cells (Swat et al, 2012). We assume that the cells bind to each other more strongly than to the fibers (Chowkwale, Mahler, Huang, & Murray, 2019). Also, the microstructure of calcified nodules in our recent study shows that mineral structures are embedded within the fibrous collagen matrix, particularly localized around fiber bundles (Mendoza et al, 2022).…”

Section: Cellular Potts Modelmentioning

confidence: 99%

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Multiscale Computational Modeling of Aortic Valve Calcification

Azimi-Boulali

Mahler

Murray

et al. 2023

Preprint

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Calcific aortic valve disease (CAVD) is a common cardiovascular disease that affects millions of peopleworldwide. The disease is characterized by the formation of calcium nodules on the aortic valve leaflets,which can lead to stenosis and heart failure if left untreated. The pathogenesis of CAVD is still notwell understood, but involves several signaling pathways, including the transforming growth factorbeta (TGFβ) pathway. In this study, we developed a multiscale computational model for TGFβ-stimulated CAVD. The model framework comprises cellular behavior dynamics, subcellular signalingpathways, and tissue-level diffusion fields of pertinent chemical species, where information is sharedamong different scales. Processes such as endothelial to mesenchymal transition (EndMT), fibrosis, andcalcification are incorporated. The results indicate that the majority of myofibroblasts and osteoblastlikecells ultimately die due to lack of nutrients as they become trapped in areas with higher levels offibrosis or calcification, and they subsequently act as sources for calcium nodules, which contributeto a polydispersed nodule size distribution. Additionally, fibrosis and calcification processes occurmore frequently in regions closer to the endothelial layer where the cell activity is higher. Our resultsprovide insights into the mechanisms of CAVD and TGFβ signaling and could aid in the developmentof novel therapeutic approaches for CAVD and other related diseases such as cancer. More broadly,this type of modeling framework can pave the way for unraveling the complexity of biological systemsby incorporating several signaling pathways in subcellular models to simulate tissue remodeling indiseases involving cellular mechanobiology.

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Section: Calcification Modelmentioning

confidence: 99%

Section: Cellular Potts Modelmentioning

confidence: 99%

Multiscale Computational Modeling of Aortic Valve Calcification

Azimi-Boulali

Mahler

Murray

et al. 2023

Preprint

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show abstract

“…Moreover, due to the lack of unified and unambiguous EndoMT read-outs on the basis of endothelial and mesenchymal characteristics, cross-comparison between different research remains challenging. With many important aspects of EndoMT remaining unexplored, using multidisciplinary and novel approaches—such as scRNA-seq, ATAC-seq, computational models, live imaging, multi-omics, bioinformatics analysis, and mathematical modeling—will help us better understand the etiology of EndoMT and provide support for the treatment of a myriad of diseases associated with EndoMT [ 103 , 104 , 129 , 148 , 152 , 153 , 154 ].…”

Section: Perspectivementioning

confidence: 99%

The Role of Endothelial-to-Mesenchymal Transition in Cardiovascular Disease

Peng

Shan

Cui

et al. 2022

Cells

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Endothelial-to-mesenchymal transition (EndoMT) is the process of endothelial cells progressively losing endothelial-specific markers and gaining mesenchymal phenotypes. In the normal physiological condition, EndoMT plays a fundamental role in forming the cardiac valves of the developing heart. However, EndoMT contributes to the development of various cardiovascular diseases (CVD), such as atherosclerosis, valve diseases, fibrosis, and pulmonary arterial hypertension (PAH). Therefore, a deeper understanding of the cellular and molecular mechanisms underlying EndoMT in CVD should provide urgently needed insights into reversing this condition. This review summarizes a 30-year span of relevant literature, delineating the EndoMT process in particular, key signaling pathways, and the underlying regulatory networks involved in CVD.

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“…wound healing, fibrosis and cancer). To study the involvement of endothelial to mesenchymal transformation in cancer progression and metastasis, Chowkwale et al 1 used a hybrid discrete–continuum approach to develop an in silico model that mimics an in vitro model.…”

Section: In Silico Model Of Endothelial To Mesenchymal Transformationmentioning

confidence: 99%

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A multiscale in silico model of endothelial to mesenchymal transformation in a tumor microenvironment

Cited by 11 publications

References 78 publications

Multiscale Computational Modeling of Aortic Valve Calcification

Multiscale Computational Modeling of Aortic Valve Calcification

The Role of Endothelial-to-Mesenchymal Transition in Cardiovascular Disease

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