Sickle cell mice cured by stem cells reprogrammed from their own tails

Stem cells have long been hyped as the shiny future of medicine. Their ability to produce to every type of cell in the body provided hope for treating diseases from Alzheimer’s, to Parkinson’s to stroke, by providing a ready supply of replacement cells. Despite years of slow progress, we are now tantalisingly close to turning this hype into reality and a new study suggests that the dawn of promised stem cell treatments is getting closer.

For the first time, scientists have cured mice of a genetic disorder called sickle cell anaemia using personalised stem cells reprogrammed from cells in their tails. The study is a powerful ‘proof-of-principle’ that reprogrammed stem cells could one day fulfil their potential in fighting human disease.

The personal touch is of the utmost importance. It’s no good just giving someone any old stem cells. Genetic differences between the donor and recipient could cause problems in the long-term and trigger attack and rejection from the hosts’ immune system in the short-term. The trick is to convert a patient’s own cells into personalised stem cells for their own private use.

Last year, a group of Japanese scientists found a way to do this in mice and produced “induced pluripotent stem cells” (iPSCs) that were very similar to embryonic stem cells. And just last month, I blogged about two breakthrough papers which showed that human cells could also be reprogrammed into iPSCs.

Now, Jacob Hanna and colleagues from the Whitehead Institute for Biomedical Research, the University of Alabama and MIT, have used these reprogrammed cells to cure a genetic disease – sickle cell anaemia.

Programming a cure

People with sickle cell anaemia lead shortened lives that are punctuated by painful attacks. The disease is caused by a single defect in the beta-globin gene that produces part of the haemoglobin protein (right).

Normally, haemoglobin shuffles oxygen around the body within our red blood cells but the faulty versions stick together, causing red blood cells to lose their oval shape and turn into rigid ‘sickles’. The damaged cells lead to anaemia, and they can clump together in blood vessels, depriving tissues of oxygen and possibly causing stroke.

The disease can be treated to minimise the symptoms, but the underlying genetic defect is always there. But Hanna’s team have managed to cure the condition, at least in mice, by editing the faulty gene in reprogrammed stem cells and injecting these back into the diseased animals (see diagram below, created by Tom DiCesare).

The team worked with a strain of mice that carried human haemoglobin genes, including the mutant version of beta-globin responsible for sickle cell anaemia. They reprogrammed cells taken from the tips of each mouse’s tail with the same method as the Japanese group. He used retroviruses to smuggle four key genes into the adult cells – Oct4, Sox2, Lif4 and c-Myc. Inside, the viruses inserted these genes into the cells’ own genetic code, triggering a suite of molecular changes that converted them into iPS cells.

The team then corrected the sickle defect in the reprogrammed cells by using a technique called homologous recombination to swap the ‘sickle’ version of the beta-globin gene with a normal one. Using a protein called HoxB4, the edited iPSCs were then converted into a more specialised type of stem cell that produces the body’s various blood cells. After this round of reprogramming, editing and priming, the stem cells were injected back into the diseased mice they originally came from.

Success and caution

After just four weeks, the levels of faulty haemoglobin in the treated mice had fallen to about a third of their former level, while the normal version dominated. Under the microscope, Hanna saw that treated individuals had red blood cells of the right number, shape and size, and far fewer deformed sickle cells. Their anaemia and kidney problems improved and they were as healthy as normal mice. The procedure was a success.

It’s a very exciting result, but it’s still too early to be blowing the victory trumpet. The method used to reprogram the cells is still problematic, not least because one of the four key genes, c-Myc, is a potential cancer gene. The team managed to cut the gene out of the iPSCs once the reprogramming was complete, but there’s still a risk that the cured mice will have a higher risk of cancer.

The retroviruses used by the team could cause similar problems; if they insert their load in the middle of important genes, the resulting faults could also lead to cancer. With more research, these viruses could be replaced with small molecules that do the same job, or engineered proteins that can immigrate into the cell on their own.

Even though research on reprogrammed stem cells is moving at a tremendous pace, Rudolf Jaenisch (the study’s principal author) warns that there’s still some way to go for this young and developing science.

Reprogramming circumvents the ethical dilemmas posed by working with fresh embryonic stem cells but Jaenisch stresses that without that research, none of the recent spate of breakthroughs would have been possible. It would be foolish to abandon this line of work now, when our knowledge of stem cells is still in its infancy.

More on stem cells:

Human skin cells reprogrammed into stem cells

Stem cells only grow up properly in the right environment

Hanna, J., Wernig, M., Markoulaki, S., Sun, C., Meissner, A., Cassady, J.P., Beard, C., Brambrink, T., Wu, L., Townes, T.M., Jaenisch, R. (2007). Treatment of Sickle Cell Anemia Mouse Model with iPS Cells Generated from Autologous Skin. Science DOI: 10.1126/science.1152092