A team of scientists have described their efforts to find compounds which can promote the regeneration of tissue, publishing in the journal Science. Using mouse models, the researchers report the identification of a drug which through targeting a specific protein was able to help tissue regeneration after colon and liver injury, and also of blood cells after bone marrow transplant.
Prof. Ilaria Bellantuono, Reader in Stem Cell and Skeletal Ageing, University of Sheffield, said:
“This is an exciting study which shows the potential of using a drug treatment to boost stem cell activity directly in the tissue where they reside. The potential of such an approach is very high. With an increasing older population the number of cancer patients is due to rise. Often these patients are not sufficiently fit to receive the full cancer treatment due to the side effects, compromising their chances of cure. Such an adjuvant treatment has the potential of boosting patents’ resilience and improving their response to cancer treatment. This study is a proof of concept in mice and more experimental work is needed to verify the long term safety of such an approach but it surely shows promise.”
Dr Dusko Ilic, Reader in Stem Cell Science, King’s College London, said:
“The drug seems to be too good to be true. The data presented show remarkable improvement in regeneration of multiple tissues. However, the study is performed only in mice and it would be encouraging to see a similar effect in other larger animal before even thinking about clinical trial in humans. What does worry me and curbs my enthusiasm is the fact that all the mouse disease models are actually otherwise healthy animals. For example, they show that after resection of two-thirds of the liver mass, mice treated with the experimental drug show increased rate of regeneration as compared with control. When would one remove 2/3 of liver in human patients? The most often is in a case of malignant tumour. Giving drug to such patients would be too risky – if any tumour cell survived, it is likely that their proliferation would be potentiated. Thus, we may end up causing more harm to the patients. The drug might be more useful in patients who have had part of their liver removed after trauma-related injury, rather than from a tumour, but the same issue would still apply and we would have to be sure that nothing else was wrong with any organ in the body.
“Also, we do not know long term effects of the drug. Would the mice be prone to tumour development after being treated with the drug? If the drug indeed works as all of us hope that it will in humans too, the use will be very limited.”
Prof. Malcolm Alison, Professor of Stem Cell Biology, Barts and The London School of Medicine and Density, Queen Mary University of London (QMUL), said:
“This is a really exciting advance in the field of regenerative medicine. The authors identified a small molecule (15-PGDH) that can inhibit the normally rapid degradation of prostaglandin E2 (PGE2, a hormone-like substance that regulates numerous metabolic functions), optimising tissue concentrations of PGE2 at beneficial physiological levels. Clinically meaningful benefits were achieved in three tissues where currently there can be life-threatening complications of inadequate or slow regeneration. Bone marrow cell transplantation is often performed after cancer chemotherapy, but the cells take time to re-establish themselves in the bone marrow, leaving the patient vulnerable to infection. 15-PGDH accelerated the whole process from cell homing to the marrow cavities to boosting production of stem cells and neutrophils to fight infection. Ulcerative colitis (UC) is a very unpleasant and potentially lethal disease for which currently there is no effective therapy. Using a mouse model of UC, 15-PGDH conferred a significant protection against ulcer formation by maintaining colonic epithelial cell proliferation in a scenario where otherwise proliferation would be greatly reduced. Finally the authors showed that 15-PGDH accelerated liver regeneration and clearly this could have life-saving implications in several situations, e.g. many liver cancer sufferers are not eligible for tumour resection because the remaining tumour-free liver would be incompatible with survival, being too small. Boosting the immediate regeneration rate after resection might well see such patients overcome this hurdle.
“Although these studies were in mice, all three models are well validated, and with no adverse side-effects in the short-term. Obviously more experimental studies are needed before early clinical trials can start, but if successful, I see no reason why such an approach cannot be translated to the clinic quite quickly. The inhibitor may also have utility in other areas of significant human morbidity, for example, diabetic leg ulcers.”
‘Inhibition of the prostaglandin-degradingenzyme 15-PGDH potentiates tissue regeneration’ by Zhang et al. published in Science on Thursday 11th June.
Prof. Ilaria Bellantuono: No conflict of interest
Dr Dusko Ilic: I have no conflict of interest
Prof. Malcolm Alison: No conflicts of interest