By Claire Sand (King's College London, UK)
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.
Shutterstock Image ID: 159873314 Copyright: Somkiat Famkee
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:
PMCID: 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 Xu
Proc. Natl. Acad. Sci. USA (2012)
109(34), 13793-13798
Access to Understanding entrants are asked to write a plain English summary of a research article. For Access to Understanding 2013 there were 9 articles to choose from, selected by the Europe PMC funders.
The articles are all available from Europe PMC, are free to read and download, and were supported by one or more of the Europe PMC funders.
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