The biology of wound healing might seem a dry subject, underwhelming to all but a specialist. But research into possible epigenetic effects in wound healing has revealed an aspect of it that is profound. The way wounds heal changes with ageing. Embryos can heal their wounds without leaving scars, but that is generally not the case in adult animals, and scarring plays a role in the progressive declining health associated with age. In other words, although scarring is a mechanism of wound healing, it can itself cause continuing medical problems (e.g. the scarring in lungs caused by pneumonia and silicosis). Livers have a notable ability to recover from wounding; they can regenerate after substantial loss or damage of tissue. This reflects the importance of liver in dealing with toxicity; it has to be good at recovering from damage itself (e.g. from toxic chemicals) if it is to provide protection for the rest of the body. The recovery from some types of liver damage does leave scarring, but the process can be plastic.
Experiments have shown that the progeny of male rats that have been exposed to a liver damaging chemical have substantially less liver scarring than their parent when exposed to the chemical themselves1. So the environmentally challenged male parents seem to have changed the wound healing response in their progeny (the effect was passed on through at least two generations). The problematic effects of scarring suggests that this transgenerational resistance to it may be an adaptation, endowing improved fitness on the progeny. Given what we have already shown in preceding examples of epigenesis, perhaps this isn’t altogether surprising. However, a clue suggesting something particularly special in this effect is that it seems restricted to liver; ancestral liver damage does not reduce chemical scarring that occurs in kidneys of toxin treated progeny. This, and other experimental evidence indicated that the environmentally induced transgenerational anti-scarring effect is highly specific to liver rather than being a general one affecting other organs. Such specificity raises a logical problem: if this process is so specific to liver, excluding other organs, how can it be transgenerational if the testes, and consequently sperm (the toxin exposed parents in these experiments were the fathers), are excluded from it? That question led the research group involved to test for a possibility that had long been considered impossible: transfer of genetic information from somatic tissue to the germ line.
Researchers took blood serum from male rats treated with toxin exactly as in the earlier experiments, having allowed a period for the animals to clear the toxin from their systems, and transfused it into other untreated male rats. They found that this exposure to the serum of toxin-exposed rats generated epigenetic changes, in the recipient rats’ sperm, to genes known to be directly involved in the scarring process. (Specifically, scarring involves a process of differentiation of a type of liver cell, stellate cells, that change into a new type called myofibroblasts; these genes are highly important in the control of that differentiation process.) The observed changes to the chromatin of these genes are very likely to alter their expression in a way that could inhibit the scarring process. So the serum recipient rats’ sperm have undergone an epigenetic change likely to make them capable of passing on an anti-scarring capability to their own progeny, even though they themselves were not exposed to the toxin.
This suggests that toxin treatment of male rats results in something being secreted into blood that carries a signal to their testes, causing epigenetic changes to genes that control aspects of liver phenotype. In this way the rats’ adult bodies have apparently conveyed an instruction to their sperm and hence to the next generation. The researchers conducted further experiments that established that the signal molecule comes from the affected organ, the liver, and specifically from the stellate cells. It appears, therefore, that an acquired alteration in the phenotype of an organ is causing changes to the hereditary material of these animals (their germline) that makes the acquired trait heritable.
”This suggests that toxin treatment of male rats results in something being secreted into blood that carries a signal to their testes … ”
This is very disruptive. Animals have a separation between the cells responsible for reproduction (the germline) and those that form the embryonically developing and adult body and organs (the somatic cells, or soma). A classic, central tenet of genetics, that, in animals, hereditary information can flow in one direction only (the “Weismann barrier”2), from the germline to the soma, has been questioned by this research. The idea of information passing in the reverse direction, from soma to germline, i.e. that the soma can change its phenotype and make those changes heritable by inducing changes in the germline, has long been considered impossible, largely because of huge difficulty to date in conceiving a biological mechanism. This experiment is highly persuasive of an inherited trait arising in a soma to germline direction, and suggests where to look for a mechanism: some kind of an information carrier transported by blood.
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References
- Zeybel, Müjdat, Timothy Hardy, Yi K. Wong, John C. Mathers, Christopher R. Fox, Agata Gackowska, Fiona Oakley, et al. ‘Multigenerational Epigenetic Adaptation of the Hepatic Wound-Healing Response’. Nature Medicine 18, no. 9 (September 2012): 1369–77. https://doi.org/10.1038/nm.2893 [↩]
- August Weismann. Das Keimplasma: Eine Theorie Der Vererbung. Jena: Fisher, 1892 [↩]