Awarded joint 2nd prize for Access to Understanding 2013
For years scientists have attempted to harness the potential of stem cells for repairing damaged blood vessels. The tendency of stem cells to cause cancer, however, has meant that progress has been limited. Now, a team from King’s College London, led by Professor Qingbo Xu, have found a way of converting skin cells into blood vessel cells, raising hopes of new and improved treatments for cardiovascular disease.
Why is this research so important?
In an age where diets are rich in fat, cholesterol and salt, smoking is prolific and people are living to an increasingly old age, our blood vessels have never been more vulnerable. Damage to the inside of our arteries (in particular an important layer of cells called endothelial cells) can lead to coronary artery disease – the main cause of death in most industrialised countries. Consequently, scientists are striving to find ways of repairing or replacing damaged blood vessels with specially engineered tissues.
How are they doing this?
Traditionally, with stem cells. These have the ability to become any cell in the human body. During foetal development, embryonic stem cells take cues from the placental environment to become specialised heart or liver cells, for example. This process is known as differentiation.
The ability of stem cells to differentiate into any other cell has long been exploited by scientists, although ethical concerns and issues of immune rejection (where the body’s immune system attacks implanted cells) have seriously limited success. In 2006, a Japanese research group found a way of avoiding these issues by reprogramming (or de-differentiating) mature skin cells back into stem cells. These so-called induced pluripotent stem cells (or iPS cells) could then be re-differentiated, using specialised conditions, into a different cell type altogether. This breakthrough raised the exciting possibility of ‘personalised therapy’. Skin cells from a patient with heart failure, for example, could theoretically be reprogrammed into heart cells that could be implanted without the risk of immune rejection.
So what’s the problem?
The main problem with iPS cells is that they can cause tumours. In order to make iPS cells, specific stem cell genes must be inserted into differentiated cells, forcing them to de-differentiate back into a stem state. Unlimited self-renewal is a key feature of stem cells, and introduction of stem cell genes into mature cells can cause them to multiply uncontrollably – just like tumour cells. Unfortunately, scientists have found that implantation of iPS cells causes cancer in a worrying number of lab mice.
What has Professor Xu’s group done differently?
De-differentiation of mature cells into iPS cells normally takes four weeks. Scientists in Professor Xu’s lab noticed that after only four days, skin cells lost their original characteristics without gaining those of a stem cell. Using specialised conditions the scientists were able to manipulate these partial iPS cells into becoming endothelial cells, which form the essential inner lining of blood vessels. Through this partial de-differentiation, they were able to eliminate the stem cell stage of reprogramming – and with it, the risk of tumour formation.
Fibroblast cells (microfilaments [blue], mitochondria [red], and nuclei [yellow])
Shutterstock Image ID: 135258320 Copyright: Heiti Paves
Are artificial endothelial cells the same as normal ones?
They have the same shape and size as endothelial cells, and contain the same unique genes. Importantly, they don’t have any of the characteristics specific to stem cells or the original skin cells, and can be used to generate artificial blood vessels in a biological simulator.
Crucially, the scientists had to test whether their endothelial cells can contribute to blood vessel repair in the body. They injected specially dyed cells into the legs of mice with artificially damaged arteries, and found that this greatly improved blood flow in the damaged legs. When the blood vessels were later dissected, the scientists found that they contained a high proportion of dyed cells. This suggests that the lab-made endothelial cells can combine with damaged tissues, and contribute to their repair. Importantly, none of the mice injected with these cells developed cancer in the time it normally takes tumours to appear.
Where will this lead?In the relatively near future, lab-made cells and blood vessels will be a valuable resource for drug toxicity screening. Being of human origin, these cells and tissues are particularly relevant to human medicine, and could significantly reduce, if not replace, the use of lab animals for such testing. By using partially de-differentiated cells rather than stem cells, the scientists have also greatly reduced the time it takes to obtain viable endothelial cells, making the technique more practical to use in patients. ‘Personalised transplantation’ is still a long way off, and more safety assessments are needed. Nonetheless, in overcoming the problem of tumour formation, this team from King’s College London have brought blood vessel engineering one step further on the route from the lab to the clinic.
This entry describes research published in the following article, selected by the British Heart Foundation:
Direct reprogramming offibroblasts into endothelial cells capable of angiogenesis andreendothelialization in tissue-engineered vesselsPMCID: PMC3427074
Andriana Margariti, Bernhard Winkler, Eirini Karamariti, Anna Zampetaki, Tsung-neng Tsai, Dilair Baban, Jiannis Ragoussis, Yi Huang, Jing-Dong J. Han, Lingfang Zeng, Yanhua Hu, and Qingbo XuProc. Natl. Acad. Sci. USA (2012) 109(34), 13793-13798
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