Integrins and cell-fate determination

Abstract

All cellular processes are determined by adhesive interactions between cells and their local microenvironment. Integrins, which constitute one class of cell-adhesion receptor, are multifunctional proteins that link cells to the extracellular matrix and organise integrin adhesion complexes at the cell periphery. Integrin-based adhesions provide anchor points for assembling and organising the cytoskeleton and cell shape, and for orchestrating migration. Integrins also control the fate and function of cells by influencing their proliferation, apoptosis and differentiation. Moreover, new literature demonstrates that integrins control the cell-division axis at mitosis. This extends the influence of integrins over cell-fate decisions, as daughter cells are frequently located in new microenvironments that determine their behaviour following cell division. In this Commentary, I describe how integrins influence cell-fate determination, placing particular emphasis on their role in influencing the direction of cell division and the orientation of the mitotic spindle.

Fig. 1.

Multiple points in the control of cell cycle and fate by integrins. The points in the cell cycle at which integrins have an essential role are shown in pink, and include G1, metaphase and telophase. The fates of daughter cells are also integrin-dependent. They become committed to (a) re-enter the cell cycle, (b) survive or apoptose or (c) express tissue-specific genes and differentiate. (d) In the case of stem cells, one daughter cell will enter the cell cycle and then undergo one of the three fates shown in (a-c), whereas the other will remain a stem cell.

Fig. 2.

Integrins orient the cell-division axis. (A) The mitotic spindle aligns along the long axis of the cell, which lies at right angles to the plane of cytokinesis. A mitotic cell is shown, and the microtubule connections between the cell edge (cortex, plasma membrane) and spindle poles, and between the spindle poles and chromosomes (which accumulate at the metaphase plate) are highlighted. (B) Cells adhere to the ECM through integrins. They can either divide along the plane of the ECM (turquoise in panels C-E) to which they adhere (x- or y-axes), or away from it (z-axis). (C,D) Tension provided along the x-axis causes unilateral extension (C), which becomes bilateral if tension is also provided in the y-axis (D), forming a sheet of cells. (E) Orientation of the plane of division along the z-axis causes cells to become displaced away from the initial ECM. These new (purple) cells have a microenvironment that is different to the parental (pink) cells. Thus, following cell division, daughter cells become located either in a similar niche to their parents, or in a new microenvironment.

Fig. 3.

Retraction fibres provide resistive forces to orient the mitotic spindle. (A) Interphase cell, showing sites of attachment to the ECM via integrin adhesions and the intracellular cytoskeleton. This is the view that is seen when looking down on cells in 2D culture. (B) Mitotic cell that has rounded up in preparation for cytokinesis. The cell remains attached to the substratum through retraction fibres, which provide resistance so that tension can build up within microtubules and thereby orient the spindle.