Cell-cycle control by physiological matrix elasticity and in vivo tissue stiffening.
BACKGROUND
A number of adhesion-mediated signaling pathways and cell-cycle events have been identified that regulate cell proliferation, yet studies to date have been unable to determine which of these pathways control mitogenesis in response to physiologically relevant changes in tissue elasticity. In this report, we use hydrogel-based substrata matched to biological tissue stiffness to investigate the effects of matrix elasticity on the cell cycle.


RESULTS
We find that physiological tissue stiffness acts as a cell-cycle inhibitor in mammary epithelial cells and vascular smooth muscle cells; subcellular analysis in these cells, mouse embryonic fibroblasts, and osteoblasts shows that cell-cycle control by matrix stiffness is widely conserved. Remarkably, most mitogenic events previously documented as extracellular matrix (ECM)/integrin-dependent proceed normally when matrix stiffness is altered in the range that controls mitogenesis. These include ERK activity, immediate-early gene expression, and cdk inhibitor expression. In contrast, FAK-dependent Rac activation, Rac-dependent cyclin D1 gene induction, and cyclin D1-dependent Rb phosphorylation are strongly inhibited at physiological tissue stiffness and rescued when the matrix is stiffened in vitro. Importantly, the combined use of atomic force microscopy and fluorescence imaging in mice shows that comparable increases in tissue stiffness occur at sites of cell proliferation in vivo.


CONCLUSIONS
Matrix remodeling associated with pathogenesis is in itself a positive regulator of the cell cycle through a highly selective effect on integrin-dependent signaling to FAK, Rac, and cyclin D1.
Klein
Eric A
EA
Department of Pharmacology, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Yin
Liqun
L
Kothapalli
Devashish
D
Castagnino
Paola
P
Byfield
Fitzroy J
FJ
Xu
Tina
T
Levental
Ilya
I
Hawthorne
Elizabeth
E
Janmey
Paul A
PA
Assoian
Richard K
RK
D000818:Animals; D001158:Arteries / Q000473:pathology / Q000648:ultrastructure; D002453:Cell Cycle; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000502:physiology; D004548:Elasticity; D005109:Extracellular Matrix / Q000502:physiology*; D051417:Focal Adhesion Kinase 1 / Q000032:analysis / Q000502:physiology; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction
D016160:Retinoblastoma Protein; D019938:Cyclin D1; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse