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Zombie Myofibroblasts


Arthrofibrosis is a form of fibrosis [1]. Fibrosis occurs when zombies appear on the internal landscape - myofibroblasts (healing cells) become senescent (aged) and persist instead of self-destructing when their job is done [2]. Any type of cell can become senescent and this is protective in the short term, but when senescent cells persist they cause a wide arrange of diseases. Some senescent cells can remain after each insult and accumulate locally, for example in a joint after each surgery. When a threshold of tolerance is breached senescent cells start to “feed” themselves [2] and things start getting nasty, with the near-immortal “zombies” spreading their sickness to healthy cells via their secretions [3].


FibroSIS looks and acts like a myofibroblast (image below) and is the central supervillain in the arthrofibrosis story, It must be vanquished before the nightmare ends and normal life can return. FibroSIS turns the inhabitants (cells) that it bites into zombie copies of itself.


Although senescence happens with aging, it can occur at any age (even in children) in cells that are exposed to chronic inflammation or repeated trauma [2]. Cells turn senescent in response to inflammation, signals from mechanically damaged cells (trauma), metabolic stresses (eg high glucose, high fat) [4,5], hypoxia and even resistance exercise [2]. Like zombies, senescent cells change dramatically, becoming enlarged and metabolically very active [6]. So, although senescent cells don’t replicate, they turn other cells into zombies, creating more senescence and damage [3]. It’s a fascinating fact that age-related diseases can by induced in young animals by transplanting senescent cells into them [7]. It turns out that life really is stranger than fiction!


The resistance of myofibroblasts to apoptosis is a key mechanism in fibrosis

In fibrosis, senescent myofibroblasts secrete many factors associated with inflammation (IL-6, IL-8, IL-1, ROS), cell proliferation and the production of extracellular matrix (scar tissue) [8], including the key fibrosis cytokine TGF-β [6]. This is known as the senescence-associated secretory phenotype (SASP). Senescent cells also secrete pro-apoptosis (kill-me) factors that make other cells self-destruct, but which they themselves are resistant to [4,7]. The resistance of myofibroblasts to apoptosis is a key mechanism in fibrosis [9]. Young animals are resistant to fibrosis because most of their myofibroblasts self-destruct after healing, allowing the clearance of scar tissue and resolution [9].


Like all good zombies, senescent cells ensure their ongoing survival with powerful feedback loops [6] and they create more inflammation and fibrosis in the process. However, their secretions often change over time [2] and in arthrofibrosis this may be experienced as a gradual reduction in pain and inflammation. The SASP also differs depending on the type of cell that is senescent and how senescence was induced [2]. We have different varieties of zombies!


Figure from Davan-Wetton et. al.: The clearance of senescent cells, efficient and timely, is required to complete the senescence programme successfully. An impaired clearance will lead to persistent action of SASP components leading to a failure of resolution [10].


So, how do we kill our zombies? Our body naturally has some answers, and caloric restriction has been shown to promote the destruction of senescent cells and extend healthy lifespan [10]. Hunter-gatherer peoples living traditional lifestyles often experience periods with no food, and intermittent fasting, including time-restricted eating, may be the most effective form of caloric restriction. Scientists are also beginning to discover a range of compounds that can help control or clear our zombie cells, and these are referred to as senolytics. Intermittent treatment with senolytics is effective because senescent cells don’t divide, and take time to re-accumulate [7]. However, different types of zombies require different compounds to knock them off, and research is ongoing to determine what is best, and when.

Several compounds that occur naturally in fruit and vegetables act as senolytics, and resveratrol, fisetin and quercetin the most effective tested so far [5 ,10, 11]. Quercetin targets the insulin/IGF-1 and hypoxia (HIF-1α) pathways [7]. Metformin, a widely used diabetes medication, inhibits inflammation from senescent cells by reducing NF-кB activation and selectively represses genes responsible for the SASP [8].


We should be very mindful not to re-awaken our sleeping zombies by doing too much too quickly

Several cancer drugs have also demonstrated their usefulness, but are not widely available. Dasatinib is a tyrosine kinase inhibitor used in treating leukaemia. The first clinical trial using Dasatinib and quercetin (DQ) in patients with lung fibrosis showed statistically significant and clinically meaningful improvements in physical function [7]. DQ decreases senescent cell burden and alleviates a range of senescence associated diseases in animals [7]. Other medications such as JAK inhibitors and rapamycin suppress expression of the SASP and reduce inflammation [10], but do not kill senescent cells [12].


For people with arthrofibrosis it’s important to remember that zombie myofibroblasts can lurk in our joints for a year or longer after an injury or surgery, so if we’re lucky enough to recover function we should be very mindful not to re-awaken our sleeping zombies by doing too much too quickly.


Please consult your doctor before starting a new supplement.


References
  1. Usher, K. M. et al. Pathological mechanisms and therapeutic outlooks for arthrofibrosis. Bone Research 7, doi:10.1038/s41413-019-0047-x (2019).

  2. Chaib, S., Tchkonia, T. & Kirkland, J. L. Cellular senescence and senolytics: the path to the clinic. Nat Med 28, 1556-1568, doi:10.1038/s41591-022-01923-y (2022).

  3. Scudellari, M. To stay young, kill zombie cells. Nature 550, 448-450, doi:10.1038/550448a (2017).

  4. Prata, L. G. P. L., Ovsyannikova, I. G., Tchkonia, T. & Kirkland, J. L. Senescent cell clearance by the immune system: Emerging therapeutic opportunities. Semin Immunol, 101275, doi:10.1016/j.smim.2019.04.003 (2019).

  5. Li, W. et al. Emerging senolytic agents derived from natural products. Mech Ageing Dev 181, 1-6, doi:10.1016/j.mad.2019.05.001 (2019).

  6. Salama, R., Sadaie, M., Hoare, M. & Narita, M. Cellular senescence and its effector programs. Genes Dev 28, 99-114, doi:10.1101/gad.235184.113 (2014).

  7. Justice, J. N. et al. Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. EBioMedicine40, 554-563, doi:10.1016/j.ebiom.2018.12.052 (2019).

  8. Lopes-Paciencia, S. et al. The senescence-associated secretory phenotype and its regulation. Cytokine117, 15-22, doi:10.1016/j.cyto.2019.01.013 (2019).

  9. Hecker, L. et al. Reversal of Persistent Fibrosis in Aging by Targeting Nox4-Nrf2 Redox Imbalance. Science Translational Medicine 6, 231ra247, doi:10.1126/scitranslmed.3008182 (2014).

  10. Davan-Wetton, C. S. A., Pessolano, E., Perretti, M. & Montero-Melendez, T. Senescence under appraisal: hopes and challenges revisited. Cell Mol Life Sci 78, 3333-3354, doi:10.1007/s00018-020-03746-x (2021).

  11. Zhu, Y. et al. New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Aging 9, 955-963, doi:10.18632/aging.101202 (2017).

  12. Laberge, R. M. et al. MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat Cell Biol 17, 1049-1061, doi:10.1038/ncb3195 (2015).

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