The best way to regrow a liver? With leprosy bacteria

The leprosy bacteria boosted the size of livers in armadillos, but kept them healthy.

The leprosy bacteria boosted the size of livers in armadillos, but kept them healthy. Photo: Getty

Leprosy is one of the oldest infectious diseases in human history, with its victims cast out of family groups and societies for centuries.

One of the freaky aspects of leprosy is its sneakiness.

For one thing, the bacteria that causes leprosy, Mycobacterium leprae, is slow growing and can take up to 20 years to incubate in a human body.

So when people seemed to suddenly develop deformities, the disease took a bad-magic status.

‘Biological alchemy’

In 2013, Edinburgh researchers, in experiments with mice, found that Mycobacterium leprae reprograms cells in the peripheral nervous system and turns them into stem-like cells.

Computer illustration of Mycobacterium leprae bacteria. Image: Getty

Some background: The peripheral nervous system is the initial target and preferred host for the parasitic Mycobacterium leprae. (Injuries eventually manifest in the skin, nose and eyes).

The leprosy bacteria specifically hijacks the genes of Schwann cells – which create a fatty sheath that insulates peripheral nerve fibres and, when healthy, help injured cells recover and regenerate.

Where the destructive numbness comes from

It’s this infection which leads to the characteristic loss of feeling in the extremities.

With all this damage being efficiently done, what’s the point of reprogramming Schwann cells into stem-like cells?

The short version: It allows the bacteria to hitch a ride around the body without being harassed by the immune system. It can then integrate with a specific muscle or organ.

“This is a stem cell that is generated by the body’s own tissue so the immune system does not recognise it and they can get any place they want without being attacked,” study leader Professor Anura Rambukkana, a regeneration biologist at the University of Edinburgh, told the BBC.

This finding was big news – with hope that the genius and mysterious reprogramming ability of the bug might somehow be harnessed by regenerative medicine.

As Professor Rambukkana told the journal Nature:

“This is a very sophisticated mechanism — it seems that the bacterium knows the mechanistic interaction of the Schwann cell better than we do.”

Startling new study

Building on that 2013 study, Professor Rambukkana has made a new discovery: The leprosy parasite’s reprogramming abilities extends to increasing the size of livers in animal hosts, and keeping them healthy.

An enlarged liver is normally seen as a symptom of poor health.

In this instance, the parasites seem to achieve what medical science has so far failed to do – use stem cells to rejuvenate animal livers without causing scarring or tumours.

How was the discovery made?

The team infected 57 armadillos, a natural host of the leprosy bacteria, with the parasite.

They then compared their livers with those from armadillos that were uninfected, and with those resistant to infection.

The infected animals developed enlarged livers that remained healthy and were completely unharmed.

Experiments in liver regeneration have been hampered with tumours. Photo: Getty

Their livers behaved normally, growing and maintaining blood vessels, bile ducts and functional units known as lobules that were as healthy as those found in the uninfected and resistant armadillos.

What’s going on here?

According to an explainer from the University of Edinburgh, the researchers believe the bacteria ‘hijacked’ the inherent regenerative ability of the liver to increase the organ’s size.

The researchers believe this is done to create more cells for infection.

But previous research, not associated with the Edinburgh work, found that liver function was in the early stages of infection in people – and it’s not unreasonable to wonder if this hijacking of the regenerative process is designed to maintain metabolic health of the host.

Other findings

The researchers found evidence that the main kinds of liver cells  – known as hepatocytes – attained a “rejuvenated” state in the infected armadillos.

The infected livers “contained gene expression patterns – the blueprint for building a cell – similar to those in younger animals and human fetal livers”.

Further, “genes related to metabolism, growth and cell proliferation were activated and those linked with ageing were down-regulated, or suppressed”.

Where, in the 2013 study, Schwann cells were found to be reprogrammed and returned to a stem-cell-like state, the scientists think a similar process is happening in infected livers.

The bacteria has reprogrammed the liver cells, “returning them to the earlier stage of progenitor cells, which in turn became new hepatocytes and grow new liver tissues”.

A graphic abstract of what’s going on with the armadillo livers. Image: Cell Reports

The possibilities

Could this discovery lead to interventions for ageing and damaged livers in people?

More than that, might the leprosy bacteria’s reprogramming process be adapted to renew ageing livers and increase health span – the length of time living disease-free?

If we can regrow damaged livers, we reduce the need for transplants, “which is currently the only curative option for people with end-stage scarred livers”.

Professor Rambukkana, lead author of a new paper, said:

“If we can identify how bacteria grow the liver as a functional organ without causing adverse effects in living animals, we may be able to translate that knowledge to develop safer therapeutic interventions to rejuvenate ageing livers and to regenerate damaged tissues.”

Excited response from independent experts

The following independent comments were provided by the Science Media Centre, edited for length. They can be found in full here.

Professor Malcolm Alison, Honorary Professor, University of Edinburgh, said:

“Ageing is one of the greatest obstacles to successful liver regeneration in people with chronic liver disease – the liver becomes senescent and fails to register the need to replenish lost tissue. This study appears to show that it is possible to reverse/reprogram this process.”

Dr Darius Widera, Associate Professor in Stem Cell Biology and Regenerative Medicine, University of Reading, said:

“Overall, the results could pave the way for new therapeutic approaches to the treatment of liver diseases such as cirrhosis.

“However, as the research has been done using armadillos as model animals, it is unclear if and how these promising results can translate to the biology of the human liver. Moreover, as the bacteria used in this study are disease-causing, substantial refinement of the methods would be required prior to clinical translation.”

Dr Zania Stamataki, Associate Professor, Centre for Liver and Gastrointestinal Research, University of Birmingham, said:

“This is a promising model and exciting research with the potential to uncover new molecular pathways for liver regeneration that may be applicable in human livers.”

The Edinburgh researchers partnered with the US Department of Health and Human Services in Baton Rouge, Louisiana.

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