Stopping senescence to regrow livers
Every year, thousands of people develop acute liver failure caused by viral infections, like hepatitis, or poisoning by drugs like paracetamol. In many cases the only way to save these individuals is with a liver transplant, but a shortage of donor organs, and the fact that often these cases often occur in resource-poor settings, means that many victims die before they can receive a new liver. But now researchers in Edinburgh have made a surprising discovery that might improve the odds considerably: they've found that many poisoned livers actually have the potential to rebuild themselves from stem cells, but they're prevented from doing so by the presence of injured cells that have switched into a state called "senescence" and begun churning out signals that make other healthy cells become senescent too, and stop growing. By blocking these signals, the ability of livers to self-repair can be dramatically improved as Katie Haylor heard from the study's lead author, Thomas Bird...
Thomas - What we were really interested in is if you have someone with acute liver failure who had a normal liver just a few days earlier, in the very sickest patients who needed liver transplants to save their lives the raw materials for regeneration are quite often there in reasonable numbers within the liver. But what was striking is they don’t seem to be proliferating, they seem to have stopped their ability to regenerate. And so we in the study were really trying to drill down and answer the question of why those cells failed to regenerate in the most severe forms of liver injury.
Katie - What did you actually do?
Thomas - First of all we examined those livers taken out of liver transplant patients, but then we got a whole series of patients who had much milder forms of injury and we graded how severe the liver injury was compared to what the biopsy taken for diagnosis of their liver disease showed. And what we were able to see was as you increased the level of injury from relatively mild to quite severe, you saw less and less proliferation of the severe end of that spectrum and we started to see the development of senescence markers. Senescence is a state of cell shock or stunning associated with permanent growth arrest which means that the regenerative cells can’t proliferate. So the idea here is you’d ideally want after large injury to have large amounts of regeneration but, unfortunately, after severe liver injury you actually stop the regenerative ability. So you’re tying it in chains in essence.
Katie - Okay. So the thinking is that this acute, severe liver injury is instigating this senescence, this zombified state of cells, and do you see this spread then throughout the liver?
Thomas - That was, I think, the most exciting features of our research which was we showed that the senescence is there at the point where injury is receding, and we were able to use genetic models to study what happens if you induce senescence in one cell to the cells in that local environment. What we were able to see was senescence could actually spread from a cell that is itself stressed to other neighbouring cells that are only responding to the cues in their environment.
So the idea here is that once senescence is established it can then spread across the liver and prevent regeneration in other areas further away from injury. The exact mechanism by which a cell that is injured induces its own senescence still needs to be clarified. And there are some exciting avenues we have in that, but we don’t know that thoroughly at the moment.
Katie - So now that you know that this senescence is spreading, what can you do about it?
Thomas - What we found was that a signaling molecule called TGF-beta is absolutely critical for that spread of senescence from injury and senescence to other uninjured cells that then become senescent. We were able to inhibit that signalling pathway and actually reduce the senescence and improve regeneration in organs. And what was key there was that we could then, in a mouse model, deliver a toxic dose of paracetamol which would otherwise be fatal, prevent the senescence, allow regeneration and those mice didn't succumb to what would otherwise be a fatal liver injury. They recovered and regenerated their livers normally. So the hope is, of course, that that would be directly translatable to humans.
Katie - Wow! So you’re kick-starting this process of regeneration. What did you use to do so?
Thomas - We started with genetic models where we could actually remove the receptor for TGF-beta specifically in the hepatocyte that would become senescent. But then we went on to use both commercially available chemicals compounds, but also with a collaboration with AstraZeneca using one of their more potent inhibitors which we then used in our preclinical studies. And that was the drug we saw the biggest clinical affect with and the survival in otherwise fatal injury models in mice.
This class of compounds inhibiting that receptor are commercially available and are in clinical trials. They’ve been through phase 1 and phase 2 in human studies in cancer, and what we’re hoping is that allows us quite quickly then to go onto clinical trials in acute liver failure to see how effective these drugs really are.
Katie - We’ve known for a while haven’t we that cell senescence can cause issues in the body, so where does the novelty with this study come in?
Thomas - Not only have we been able to show that acute damage to an organ produces senescence, and what that means is that any injury in any other organ may potentially have the same response. But the other critical thing is that the senescence actually spreads from cell to cell and we’ve been able to show that in a living animals for the first time. And so what we know have is a mechanism that allows that senescence to spread themselves from cell to cell, but we can then attack therapeutically and develop clinical compounds.