Abstract
Cell polarization plays a crucial role in dynamic cellular events, such as cell proliferation, differentiation, and directional migration in response to diverse extracellular and intracellular signals. Although it is well known that cell polarization entails highly orchestrated intracellular molecular reorganization, the underlying mechanism of repositioning by intracellular organelles in the presence of multiple stimuli is still unclear. Here, we show that front-rear cell polarization based on the relative positions of nucleus and microtubule organizing center is precisely controlled by mechanical interactions including cellular adhesion to extracellular matrix and nucleus-cytoskeletal connections. By modulating the size and distribution of fibronectin-coated adhesive spots located in the polarized cell shape mimicking micropatterns, we monitored the alterations in cell polarity. We found that the localization of individual adhesive spots is more dominant than the cell shape itself to induce intracellular polarization. Further, the degree of cell polarization was diminished significantly by disrupting nuclear lamin A/C. We further confirm that geometrical cue-guided intracellular polarization determines directional cell migration via local activation of Cdc42. These findings provide novel insights into the role of nucleus-cytoskeletal connections in single cell polarization under a combination of physical, molecular, and genetic cues, where lamin A/C acts as a critical molecular mediator in ECM sensing and signal transduction via nucleus-cytoskeletal connection.
| Original language | English |
|---|---|
| Article number | 120548 |
| Journal | Biomaterials |
| Volume | 268 |
| DOIs | |
| Publication status | Published - 2021 Jan |
Bibliographical note
Funding Information:The authors thank members of the Applied Mechanobiology Group (AMG) at Korea University for constructive discussion of cellular mechanobiology. The authors thank Professor Won Do Heo (Korea Advanced Institute of Science and Technology, Korea) for obtaining Raichu-Cdc42 with permission from Professor Michiyuki Matsuda (Kyoto University, Japan). This work was supported by the KU-KIST Graduate School of Converging Science and Technology Program. D.K. was supported by National Research Foundation of Korea ( NRF-2019R1A2C2004437 and 2020R1A4A3079755 ) and the MSIT (Ministry of Science and ICT) , Korea, under the ICT Creative Consilience program ( IITP-2020-0-01819 ) supervised by the IITP (Institute for Information & communications Technology Planning & Evaluation).
Funding Information:
Enlarged focal adhesions generate elevated intracellular tension, where phosphorylation of FAK and paxillin is increased [66]. Since higher stress induced by large focal adhesions ultimately induces recruitment of mechanosensitive ?-smooth muscle actin to cytoplasmic ?-actin filament bundles [66], adjustment of focal adhesion size could alter physical regulation of cell behaviors such as cell polarization and migration by remodeling of cytoskeletal architecture. Moreover, considering that the average length of vinculin is around 4.5 ?m in randomly spread cells [44], cells placed on adhesion size-controlled arrays could not reach their maximum cell spreading size [66]. Consistent with those previous studies, shape-unconfined randomly spread cells did not reach their maximum cell spreading size if FN island size was smaller than the focal adhesion size (red curve corresponding to 3 ?m FN islands, Fig. 1E). However, shape-guided cells displayed their maximum available size even though underlying FN island size was smaller than their focal adhesion size (see red curve corresponding to 3 ?m FN islands in Fig. 1K). These results revealed that cell shaping was also involved in establishment of cell polarization but its effect was relatively weaker than guidance of cell-ECM contact size. However, this behavior was not detected if the adhesive spot was extremely small (e.g., 1 ?m FN islands in Fig. 1K), which further supported the notion that cell confinement by mimicking polarized cell shape could promote cell spreading by modulating cell-ECM contact size.The authors thank members of the Applied Mechanobiology Group (AMG) at Korea University for constructive discussion of cellular mechanobiology. The authors thank Professor Won Do Heo (Korea Advanced Institute of Science and Technology, Korea) for obtaining Raichu-Cdc42 with permission from Professor Michiyuki Matsuda (Kyoto University, Japan). This work was supported by the KU-KIST Graduate School of Converging Science and Technology Program. D.K. was supported by National Research Foundation of Korea (NRF-2019R1A2C2004437 and 2020R1A4A3079755) and the MSIT (Ministry of Science and ICT), Korea, under the ICT Creative Consilience program (IITP-2020-0-01819) supervised by the IITP (Institute for Information & communications Technology Planning & Evaluation).
Publisher Copyright:
© 2020
Keywords
- Cell adhesion
- Cell polarization
- Lamin A/C
- MTOC
- Microcontact printing
- Nucleus positioning
ASJC Scopus subject areas
- Biophysics
- Bioengineering
- Ceramics and Composites
- Biomaterials
- Mechanics of Materials