Tissue Repair: Make Me a Salamander

14. June 2016
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Australian researchers have discovered a new technique for obtaining stem cells. With it they want to heal sick or injured tissue. Amphibians served as a model for the process, since they can easily regrow severed limbs.

Once a newt or salamander is injured, its body reacts with an amazing trick: severed legs or even damaged organs simply regrow. The mechanism behind this has now been copied by Australian scientists [Paywall]. Using a newly developed method, they hope in the future to be able to replace human tissue.

A team of researchers led by haematologist John E. Pimanda at the University of New South Wales have succeeded in reprogramming bone and fat cells such that they developed stem cell properties. Induced multipotent stem cells (iMS) was the name they thus gave to the generated cell lines. The iMS cells are supposed to differentiate anew at the site of injury into each of the cell types needed to replace damaged tissue: this is the researchers’ basic concept. The inspiration for their technique was delivered to the scientists by nature. This is because a similar thing occurs in salamanders and newts, which allow their limbs to grow anew after injury. ln amphibians tissue cells also go through a regress process until they once again have stem cell-like properties. The renewed differentiation then creates the tissue for new limbs or damaged organs.

Healing damaged tissue

With the current research approach, it’s not in the first place really about renewing limbs. Rather, it’s about healing tissue damaged by illness, injury or age. Until now, attempts have been made to promote wound healing using mesenchymal stem cells derived from adult bone marrow. These cells are multipotent, which means that they can still differentiate into different lines of tissue cells themselves. However, unlike embryonic stem cells, they cannot mature into any and every cell type of the body. They are predefined to form either bone, cartilage, muscles, ligaments, tendons or fat tissues. So far there has been little evidence that treatment using mesenchymal stem cells contributes directly to tissue regeneration, say the researchers of the University of New South Wales. The new iMS-derived cells on the other hand are capable of doing this.

For their study, the Australian researchers isolated adult osteocytes and adipocytes from mice as well as isolating adult human adipocytes. The scientists treated these cell lines with the growth factor PDGF-AB and the substance 5-azacytidine (AZA). This nucleoside analogue is used in leukemia therapies, but it is also known that it promotes cell plasticity. By treating the cell lines with AZA, the scientists hoped to enable cells to transition into a multipotent state. Through its combination with the growth factor, the researchers hypothesise, one would end up obtaining malleable proliferating cells.

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Human experimental trials in 2017

As the results showed, the cells treated with PDGF-AB and AZA cells actually partially differentiated and developed features that resembled those of mesenchymal stem cells again. Furthermore, the researchers were able to show that osteocytes treated in this way in their stem cell-like state contributed to tissue regeneration in mice. At present, tests are now being conducted to see whether human fat cells reprogrammed as iMS cells can safely repair damaged tissue from mice, according to John E. Pimanda in a press release. First trials with humans would then likely take place at the end of 2017.

Ralph Mobbs, a neurosurgeon at the University of New South Wales, is likely to be leading this array of human experiments. He emphasised the opportunities that come with the new method. Therapy involving the iMS cells have “enormous potential” to be able to treat back and neck pain, disc injuries and muscle degeneration. In addition it could promote healing after complicated operations, he says. It was hoped that the new type of cells could promote the fusion of spinal implants with bones, something which has until now not always worked well, Mobbs added.

Tumour-forming potential?

Basically the idea of reprogramming adult cells into stem cells is not new. Doing much the same, Japanese researcher Shinya Yamanaka and Briton John B. Gurdon obtained the Nobel Prize for pioneering research in this field in 2012. Just six years earlier Yamanake managed to obtain stem cells from adult mouse cells. He, however, used a completely different method. Unlike the researchers in New South Wales, Yamanaka introduced genes into the cells using viruses in order to reprogram them. And unlike the Australian researchers, Yamanaka generated artificial pluripotent stem cells (induced pluripotent stem cells). Such cells can, similarly to embryonic but unlike multipotent stem cells, differentiate into all possible cell types of the body. Pluripotent stem cells however carry the potential to form teratomas.

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Lead author and discoverer of the technique. Vashe Chandrakanthan. © Unsw media

 The lead author of the Australian study and developer of the new technology, Vashe Chandrakanthan, stressed in the press release that the iMS method has advantages over other forms of stem cell therapy and stem cell generation. Due to their tumorigenic potential, embryonic stem cells cannot be used as such to repair damaged tissue. And the use of viruses for stem cell generation is unacceptable in clinical use as well. “We believe that we have overcome such difficulties through the new technique”, Chandrakanthan says.

Proof supporting the fact that the application of iMS does not really carry any dangers has however not yet arrived. There is, it’s true, after a mere 12 weeks still no indication of the cells showing tumorigenic potential, the authors write in the study discussion. Before using the method in the clinical world though, it remains important as ever to evaluate the long-term effects.

Original publication:

PDGF-AB and 5-Azacytidine induce conversion of somatic cells into tissue-regenerative multipotent stem cells [Paywall]
Vashe Chandrakanthan et al.; Pnas, doi: 10.1073/pnas.1518244113; 2016

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Physiotherapist

Just imagine the potential on behalf of cartilage repair! Al those worn out knees, hips, shoulders, ankles,…
On the other hand it might be bad news (sic) for knee and hip prothese manufacturers all over the world.
Start producing blue tooth aspirators ….

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