Cell volume expansion regulates cell mechanotransduction in 3D microenvironments
Abstract/Contents
- Abstract
- In tissues, such as cartilage, marrow, and bone, cells are tightly surrounded by viscoelastic extracellular matrices (ECMs). These surrounding extracellular matrices may physically influence normal cellular behaviors such as matrix degradation, matrix deposition, differentiation, and migration, which are all critical to tissue regeneration and maintenance of health. However, little is known about the physical interactions between cells and ECMs that underlie the impact of ECM viscoelasticity on these cellular behaviors. Here, we showed the important role of volume expansion as a novel mechanism of how cells sense and respond to the viscoelasticity of the surrounding matrix. First, chondrocytes, sole cells generating cartilage matrix, were examined to understand the impact of volume expansion and matrix viscoelasticity on cellular function and disease progression. Restricted volume expansion of chondrocytes by the spatial confinement activated a pro-inflammatory phenotype of chondrocytes, consequently leading to osteoarthritic phenotypes. In contrast, viscoelastic matrix exhibiting fast stress relaxation allows the cells to form interconnected cartilage matrix and to expand their volume, leading to healthy chondrogenic phenotype. Mechanistically, we found that mechanical confinements of the surrounding matrix regulate volume expansion and intracellular calcium levels, consequently, control the chondrocytes phenotype through a TRPV4-GSK3β signaling axis. Also, we found that the TRPV4-GSK3β signaling axis is impaired in osteoarthritic chondrocytes, so that the OA cells cannot sense and respond matrix viscoelasticity. Next, we examined how cell volume regulates osteogenic differentiation of mesenchymal stem cells (MSCs) in 3D microenvironments. MSCs undergo volume expansion in fast relaxing matrices, and expansion in turn promotes MSC osteogenic differentiation. Osteogenic differentiation is reciprocally regulated by both volume expansion and activation of TRPV4 ion channels which increased nuclear translocation of RUNX2. Finally, the role of cell volume expansion for MSCs 3D migration was investigated. We found a physical mechanism that stem cells use to generate migration paths in 3D microenvironments that are confining and have no pre-existing migration paths. In these microenvironments, stem cells first extend protrusions, which subsequently expand due to movement of the nucleus into the protrusion and influx of ions into the protrusion, opening up a migration path for the cell to migrate through. Together, these findings highlight the remarkable role of volume expansion in essential physiological behaviors including such as cell function, disease progression, differentiation, and even migration in 3D microenvironments
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2020; ©2020 |
| Publication date | 2020; 2020 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Lee, Hong-pyo |
|---|---|
| Degree supervisor | Chaudhuri, Ovijit |
| Thesis advisor | Chaudhuri, Ovijit |
| Thesis advisor | Bhutani, Nidhi |
| Thesis advisor | Levenston, Marc Elliot |
| Degree committee member | Bhutani, Nidhi |
| Degree committee member | Levenston, Marc Elliot |
| Associated with | Stanford University, Department of Mechanical Engineering. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Hong-pyo Lee |
|---|---|
| Note | Submitted to the Department of Mechanical Engineering |
| Thesis | Thesis Ph.D. Stanford University 2020 |
| Location | electronic resource |
Access conditions
- Copyright
- © 2020 by Hong-pyo Lee
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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