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.
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.
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.