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Micropatterning of Single Endothelial Cell Shape Reveals a Tight Coupling between Nuclear Volume in G1 and Proliferation

Pere Roca-Cusachs ^* , Jordi Alcaraz , Raimon Sunyer ^*, Josep Samitier  , Ramon Farré ^* ¶ and Daniel Navajas ^*  ¶

^* Unitat de Biofísica i Bioenginyeria, Universitat de Barcelona-IDIBAPS, Barcelona, Spain; Institut de Bioenginyeria de Catalunya (IBEC), Barcelona, Spain; Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California; Departament d'Electrònica, Universitat de Barcelona, Barcelona, Spain; and ^¶ CIBER Enfermedades Respiratorias, Bunyola, Spain

Correspondence: Address reprint requests to Prof. Daniel Navajas, Unitat de Biofísica i Bioenginyeria, Facultat de Medicina, Universitat de Barcelona, Casanova 143, 08036 Barcelona, Spain. Tel.: 34-934-024-515; Fax: 34-934-035-278; E-mail: dnavajas{at}ub.edu.

Shape-dependent local differentials in cell proliferation are considered to be a major driving mechanism of structuring processes in vivo, such as embryogenesis, wound healing, and angiogenesis. However, the specific biophysical signaling by which changes in cell shape contribute to cell cycle regulation remains poorly understood. Here, we describe our study of the roles of nuclear volume and cytoskeletal mechanics in mediating shape control of proliferation in single endothelial cells. Micropatterned adhesive islands were used to independently control cell spreading and elongation. We show that, irrespective of elongation, nuclear volume and apparent chromatin decondensation of cells in G1 systematically increased with cell spreading and highly correlated with DNA synthesis (percent of cells in the S phase). In contrast, cell elongation dramatically affected the organization of the actin cytoskeleton, markedly reduced both cytoskeletal stiffness (measured dorsally with atomic force microscopy) and contractility (measured ventrally with traction microscopy), and increased mechanical anisotropy, without affecting either DNA synthesis or nuclear volume. Our results reveal that the nuclear volume in G1 is predictive of the proliferative status of single endothelial cells within a population, whereas cell stiffness and contractility are not. These findings show that the effects of cell mechanics in shape control of proliferation are far more complex than a linear or straightforward relationship. Our data are consistent with a mechanism by which spreading of cells in G1 partially enhances proliferation by inducing nuclear swelling and decreasing chromatin condensation, thereby rendering DNA more accessible to the replication machinery.