Myofibroblasts

Myofibroblasts “are” fibrosis – fibrosis can’t occur without them. In a healthy situation they’re the “fixers” of the body that only appear after an injury or surgery (an insult)1. Following the insult tissue becomes inflamed and local immune cells release inflammatory cytokines and factors2. These activate fibroblasts and transform them from being their normal, easy-going selves into myofibroblasts, something very different, in a Jekyll and Hyde scenario. The newly made myofibroblasts create scar tissue (collagen, or ECM), become strongly contractile and form adhesions.

Normally myofibroblasts disappear after they have done their work of making scar tissue1 and healing the wound. However, if there is an ongoing inflammatory stimulus then myofibroblasts can create a feedback effect and keep themselves activated3. They can then become immortal, much like cancer cells do, and continue to create scar tissue, TGF-β and inflammatory cytokines.

Fibrosis. When this happens it’s referred to as fibrosis. Fibrosis can occur in any organ as well as skin and eyes, and is responsible for around 45 % of all deaths3. Activated myofibroblasts keep creating scar tissue, contractions and adhesions, compromising the function and structure of the tissue and reducing range of motion of joints. This is why it’s thought to be important to keep gently stretching affected joints passively (that is, without muscle activation) every day.

The extent to which each of these processes occurs depends on the amount of inflammation present and the specific cytokines and other inflammatory signals that are present in the joint or organ2. Early after the insult it’s likely that inflammatory signals will be very strong, and there will be a lot of adhesions, scar tissue creation and contraction. As time goes by, and with the right treatment, inflammation should decrease along with these processes. However, due to the scar tissue that is already present a lack of normal ROM will persist for some time. During this period it’s important not to inflame the joint again, which can be difficult because the tissues in the joint may be stiff and delicate, and therefore easily injured.

Permanent fibrosis. If inflammation continues for too long it becomes impossible to reverse myofibroblast activation. Exactly when this is, is not known, and may vary depending on tissue type and environment. The resolution of shoulder fibrosis seems to be more common than the resolution of knee fibrosis, perhaps because shoulders can be more effectively protected from further injuries compared to knees – however, research into this is lacking. Knees, by their nature, are “hammered” from daily activities such as walking and taking stairs.

Although there isn’t good research to establish definitive time lines for resolution it seems that it’s necessary to stop the inflammatory processes that keep myofibroblasts activated in the first year after insult. After this time the scar tissue is cross-linked and stiff, and the feedback effects are well established. At present there are no known cures. While surgery helps some people it runs the real risk of making things worse by creating more inflammation. This risk appears to be higher for people with already high levels of pain and inflammation, but again, quality research is lacking.

References

1     Hinz, B. Myofibroblasts. Exp Eye Res 142, 56-70, doi:10.1016/j.exer.2015.07.009 (2016).

2     Weiskirchen, R., Weiskirchen, S. & Tacke, F. Organ and tissue fibrosis: Molecular signals, cellular mechanisms and translational implications. Mol Aspects Med 65, 2-15, doi:10.1016/j.mam.2018.06.003 (2019).

3      Hinz, B., McCulloch, C. A. & Coelho, N. M. Mechanical regulation of myofibroblast phenoconversion and collagen contraction. Exp Cell Res 379, 119-128, doi:10.1016/j.yexcr.2019.03.027 (2019).