The liver has an extensive regeneration capacity compared to other organs. However, repetitive injury—for instance, from chronic viral infection or the increasingly common nonalcoholic fatty liver disease—can lead to severe long-term damage for which the only treatment is organ transplantation.
One of the challenges in tissue regeneration is to induce organ growth without also bringing about tumor formation or other abnormalities. A new study published today (November 15) in Cell Reports Medicine suggests that bacteria causing leprosy may hold the key to boosting the organ’s regenerative capacity. Specifically, the authors found that nine-banded armadillos (Dasypus novemcinctus) infected with Mycobacterium leprae developed enlarged livers without any visible damage.
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“I think this is clear proof that there’s [regenerative] mechanisms that we weren’t aware of that are happening in mammals,” says Nina Tirnitz-Parker, a liver disease and regeneration researcher at the Curtin Medical School and Curtin Health Innovation Research Institute in Australia. In this case, after years of evolutionary coexistence, “bacteria have figured out how to” induce healthy organ growth in their hosts without damaging them, she says. Tirnitz-Parker was not involved in this study but collaborates with one of its coauthors on a separate project.
Armadillos are far from being an ideal model organism for studying liver regeneration. The new study is rather the result of a series of serendipitous events, explains coauthor Tim Kendall, a liver pathologist at the University of Edinburgh who consults for the macrophage cell therapy company Resolution Therapeutics. Kendall says he became involved in the project after being contacted by Anura Rambukkana, also at the University of Edinburgh, who asked him to look at some armadillo livers infected by M. leprae. They all looked normal, Kendall recalls.
Rambukkana’s team has long studied leprosy in armadillos, one of the few animals that are known to be infected by the bacteria. In 2013, the team reported that M. leprae was able to reprogram the animals’ adult Schwann cells, which are part of the peripheral nervous system and the bacterium’s preferred host niche, to a stem cell–like state. A later observation of enlarged but apparently healthy livers in infected armadillos prompted Rambukkana and his colleagues to contact Kendall. (Unlike in humans, where M. leprae resides mainly in the skin and peripheral nerves, in armadillos, which have a cooler core temperature, the bug can also find a niche internally.)
Kendall, Rambukkana, and their colleagues first made a series of detailed analyses on livers removed from armadillos that had been infected for 10 to 30 months. The liver-to-body-weight ratio was significantly higher in these animals compared to that of uninfected or naturally resistant armadillos. But even though the infected livers had grown, their physical parameters indicated they were otherwise normal, as Kendall had suspected when he first looked at them.
I think this is clear proof that there’s [regenerative] mechanisms that we weren’t aware of that are happening in mammals.
–Nina Tirnitz-Parker, Curtin Medical School and Curtin Health Innovation Research Institute
A healthy liver, he explains, shows a “neat organization of hepatocytes in plates” together with a characteristic placement of the specialized blood vessels that feed these cells. A healthy size increase would involve not only increased cell division, but retaining the integrity of the whole microarchitecture, he notes. The enlarged infected livers fulfilled all these characteristics and, furthermore, showed molecular and cellular markers indicative of normal functionality. They had no signs of fibrosis, tumors, or other damage, the study authors report.
Analysis of the infected livers’ gene expression showed upregulation of genes associated with fetal and adult liver progenitor–like markers and with regenerative and anti-aging patterns. Rambukkana, Kendall, and their coauthors ascribe the enlargement they observed to bacterial reprogramming of liver cells into progenitor-like cells—a similar process to that occurring in Schwann cells. In their 2013 paper, the authors found that this reprogramming triggered a series of events that promoted the bacteria’s migration and helped them spread infection. Cell proliferation and dedifferentiation in the liver may similarly assist the bacteria in propagating within their host, the authors hypothesize.
It is remarkable that the liver of these infected armadillos grows without inducing tumorigenesis, says Meritxell Huch, a stem cell and organoid researcher at the Max Planck Institute of Molecular Cell Biology and Genetics in Germany who did not participate in the study. But she notes that observations of these animals over longer periods of time are needed.
Nine-banded armadillos have a lifespan of about 12 years in the wild and 20 years in captivity, and it remains to be tested whether after 30 months there are signs of damage in their livers. If infected livers remain healthy over such long periods, then figuring out how to fine-tune tissue regeneration without inducing tumorigenesis, as these bacteria are doing, may help to eventually improve the regeneration capacity of patient organs, adds Huch, who is coinventor on patents for culturing liver organoids.
So far, how this bacterium achieves the reprogramming that leads to healthy liver growth remains a mystery. Both nine-banded armadillos and M. leprae are not classic research models in the field and, therefore, many molecular tools to study them are lacking, Kendall explains. The team has plans to unravel these mechanisms in the future. If researchers can understand how bacteria switch on these programs and find a way to do so without using the bacteria, “that would be a tremendously interesting and potentially . . . important therapeutic direction,” he says.