Calcium flickers steer cell migration

Abstract

Directional movement is a property common to all cell types during development and is critical to tissue remodelling and regeneration after damage1,2,3. In migrating cells, calcium has a multifunctional role in directional sensing, cytoskeleton redistribution, traction force generation, and relocation of focal adhesions1,4,5,6,7. Here we visualize high-calcium microdomains (‘calcium flickers’) and their patterned activation in migrating human embryonic lung fibroblasts. Calcium flicker activity is dually coupled to membrane tension (by means of TRPM7, a stretch-activated Ca2+-permeant channel of the transient receptor potential superfamily8) and chemoattractant signal transduction (by means of type 2 inositol-1,4,5-trisphosphate receptors). Interestingly, calcium flickers are most active at the leading lamella of migrating cells, displaying a 4:1 front-to-rear polarization opposite to the global calcium gradient6. When exposed to a platelet-derived growth factor gradient perpendicular to cell movement, asymmetric calcium flicker activity develops across the lamella and promotes the turning of migrating fibroblasts. These findings show how the exquisite spatiotemporal organization of calcium microdomains can orchestrate complex cellular processes such as cell migration.

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Figure 1: Calcium flickers in migrating fibroblasts.
Figure 2: Triggering calcium flickers by TRPM7.
Figure 3: Amplifying TRPM7 calcium flickers by store calcium release through type 2 Ins(1,4,5)P 3 receptors.
Figure 4: Traction force generation and calcium flicker activity.
Figure 5: Calcium flickers steer fibroblast turning.

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Acknowledgements

We thank I. C. Bruce, X. Zhu, J. J. Ma, H. Q. Cao, J. Liu, M. Zheng, X. D. Fu and R. P. Xiao for discussions, and M. Gorospe, Z. C. Liang, Q. Du, C. M. Cao, H. Huang, X. M. Lan, N. Lin, Y. R. Wang, R. S. Song and Y. Zhang for technical support. Special thanks to X. D. Fu for making his laboratory facility available to us. This work was supported by the Major State Basic Research Development Program of China (2007CB512100), and the National Natural Science Foundation of China (30630021 and 30800371) and an NIH grant (HL090905).

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Correspondence to Chaoliang Wei or Heping Cheng.

Supplementary information

Supplementary Information

This file contains Supplementary Methods, Supplementary Figures 1-11 with Legends, Supplementary Tables 1-2 and a Supplementary Reference (PDF 750 kb)

Supplementary Movie

Supplementary Movie 1 shows Calcium flickers occurring in a migrating human embryonic lung fibroblast (WI-38). 30 consecutive Confocal images were compressed to 3.0 second video (10 frames per second). Left panel is DIC transmission part, which shows the motile of a fibroblast. Middle panel is fluo-4 fluorescence part, which shows Calcium flickers occurring during the fibroblast migrating. Right panel is the merged part. (AVI 2628 kb)

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Wei, C., Wang, X., Chen, M. et al. Calcium flickers steer cell migration. Nature 457, 901–905 (2009). https://doi.org/10.1038/nature07577

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