Introduction to Mechanobiology

We're finally on to our last topic in this unit: cell signalling! More specifically, we are going to learn about mechanobiology, or how external mechanical forces affect cells.

Cells can form adhesions with other cells and with the extracellular matrix (ECM). These adhesions allow them to "feel" the stiffness and other mechanical properties of their surroundings. There are many consequences of their ability to "feel" the ECM, such as durotaxis (the tendency of cells to migrate from a softer ECM to stiffer ECM) and control of differentiation (stem cells cultured on softer ECM tend to be more likely to become brain or fat, whereas on stiffer ECMs they may become muscle or even bone). Cells can also exert force on the ECM by pulling on it.

The mechanical properties of the ECM are in part determined by its composition. ECM can consist of a variety of proteoglycans, such as aggrecan, as well as proteins, such as collagen and fibronectin. The composition of the ECM can differ from tissue to tissue and may also differ in certain conditions. Here are a few conditions that may affect the composition of the ECM (using epithelial tissue as an example):

• Ageing: Cell-cell junctions can become weak and the basement membrane (of epithelium) becomes thinner. There is increased cross-linking of ECM proteins, resulting in an increase in stiffness.
• Injury: During an injury, when endothelial cells are damaged, a clot fills the gap. Lots of collagen, mainly produced by myofibroblasts, surrounds the injury site. This also increases the stiffness at an injury site.
• Tumour: Epithelial cells become more mesenchymal. As mesenchymal cells don't care as much about their neighbours as epithelial cells, they may depart and start migrating through the matrix.

The properties of the ECM can affect the differentiation of stem cells. As I mentioned earlier, stiffness is one property that can affect stem cell differentiation. Shape can also affect differentiation: seeding cells onto small, circular sections of collagen is more likely to result in adipocytes, whereas seeding cells onto larger, square sections of collagen is more likely to result in osteocytes. Topography (i.e. the bumpiness of the ECM surface) also has an impact: smoother ECM did not appear to affect differentiation, whereas a rough ECM was more likely to produce osteocytes (bone cells).

The effects of ECM on cell differentiation may be the reason why stem cell therapies in myocardial infarction (heart attack) have so far been unsuccessful. Undifferentiated stem cells, when delivered to the site of the lesion, may even form bone due to the high stiffness in this area. Another option would be to differentiate stem cells before delivering them to the patients, but as yet getting cells to differentiate the way we want them to has still been a challenge. Understanding factors that govern cell differentiation (including stiffness) may help with this.

This lecture ended with a few slides on mechnotransduction, but we didn't get to go through all of them because time ran out. (We will go into them in more detail later on though.) For now, it's probably enough to know what connects the ECM to the nucleus, as these connections may ultimately result in gene transcription and some of the effects that we've explored so far (like stem cell differentiation). β-integrin connects the ECM to proteins such as talin and vinculin (which you might remember from one of my smooth muscle posts), which connect to actin, which connect through some other proteins (the slide says Nesprin 1, 2 and 3) to the nuclear membrane.

In the next post, we will be looking more at mechanotransduction in smooth muscle. Stay tuned!