Research Papers:

Local 3D matrix confinement determines division axis through cell shape

Lijuan He _, Weitong Chen, Pei-Hsun Wu, Angela Jimenez, Bin Sheng Wong, Angela San, Konstantinos Konstantopoulos and Denis Wirtz

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Oncotarget. 2016; 7:6994-7011. https://doi.org/10.18632/oncotarget.5848

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Lijuan He1,2, Weitong Chen1, Pei-Hsun Wu1,2, Angela Jimenez1,2, Bin Sheng Wong1,2, Angela San1, Konstantinos Konstantopoulos1,2,3, Denis Wirtz1,2,3

1Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland 21218, USA

2Johns Hopkins Physical Sciences - Oncology Center, The Johns Hopkins University, Baltimore, Maryland 21218, USA

3Departments of Oncology and Pathology and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

Correspondence to:

Lijuan He, e-mail: [email protected]

Denis Wirtz, e-mail: [email protected]

Keywords: 3D matrix, elongated cell division, long-axis rule, matrix confinement

Received: September 16, 2015     Accepted: October 03, 2015     Published: October 15, 2015


How the division axis is determined in mammalian cells embedded in three-dimensional (3D) matrices remains elusive, despite that many types of cells divide in 3D environments. Cells on two-dimensional (2D) substrates typically round up completely to divide. Here, we show that in 3D collagen matrices, mammalian cells such as HT1080 human fibrosarcoma and MDA-MB-231 breast cancer cells exhibit division modes distinct from their Counterparts on 2D substrates, with a markedly higher fraction of cells remaining highly elongated through mitosis in 3D matrices. The long axis of elongated mitotic cells accurately predicts the division axis, independently of matrix density and cell-matrix interactions. This 3D-specific elongated division mode is determined by the local confinement produced by the matrix and the ability of cells to protrude and locally remodel the matrix via β1 integrin. Elongated division is readily recapitulated using collagen-coated microfabricated channels. Cells depleted of β1 integrin still divide in the elongated mode in microchannels, suggesting that 3D confinement is sufficient to induce the elongated cell-division phenotype.

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