Media Coverage : European Science Foundation

Media Coverage

Second EuroSTELLS Workshop, 30 Sep-3 Oct 2007

Article 1 (released 17 October 2007)

Stem cell research marches on

Stem cell research proceeds apace, but many challenges lie ahead. Significant strides are being made in fundamental stem cell research in laboratories across the world, but many hurdles remain to be overcome before stem cells are routinely used to treat diseases. This was one of the main messages to emerge from an international meeting of stem cell biologists held in Milan (30 Sep – 2 Oct, “Challenges in Stem Cell Differentiation and Transplantation”) and organised by the European Science Foundation’s EuroSTELLS programme in conjunction with one of ESF’s Member Organisations, the National Research Council (CNR) of Italy.

Stem cell therapy promises to open up a new way to treat diseases by growing new tissues and organs from stem cells – ‘blank’ cells that have the potential to develop in many different types of cell, also known as ‘toti-’ or ‘pluripotent’ cells. Stem cells exist in many tissues of the body, constantly replenishing dying cells, but cells that have most potential are those derived from embryos. The EuroSTELLS programme aims to develop a stem cell ‘toolbox’ by generating fundamental knowledge on stem cell biology.

The conference in Milan heard of many significant advances in the field. Dr. Michel Pucéat of the French National Institute of Health and Medical Research (Inserm) described promising new results in the use of stem cells to treat damaged heart tissue in animal models . Embryonic stem cells were first treated with a special compound known to prime the cells into becoming heart muscle cells. The cells were then seeded onto damaged heart tissue, where they proceeded to develop into heart muscle cells and restore some of the cardiac function.

Professor Ernest Arenas, a EuroSTELLS collaborator at the Karolinska Institute in Stockholm explained how stem cells could be used to treat Parkinson’s disease, which is characterised by the loss of a particular type of brain cell called dopaminergic neurons in the part of the brain called the substantia nigra. There has been some success in treating the disease by transplanting cells from foetuses into the brain, but, as Professor Arenas said, “One of the big problems with this kind of transplantation is availability of tissue. We need to get better material for transplantation and I think everyone agrees nowadays that the material will be stem cells.”

Professor Arenas’s research group has identified a particular class of protein molecules, called the Wnt family, which can coax stem cells into becoming dopaminergic cells, and when these cells are transplanted into the brain tissue of animals that have a condition similar to Parkinson’s disease, there is a significant restoration of the brain’s function .
Dr. Gianvito Martino of the San Raffaele Hospital in Milan pointed out that it is often difficult to integrate new cells that have derived from stem cells into existing tissues – a problem that is particularly significant with adult stem cells. Nevertheless, the new cells can still exert a profound influence on the existing neighbours – a so-called bystander effect.

Dr. Martino’s team has been working with a type of cell called adult neural precursor cells which, interestingly, possess significant immunological characteristics making them resemble immune cells. One effect of this is that when injected into a body, the cells automatically home in on inflamed tissue. In multiple sclerosis, for example, the cells find their way to damaged nerve cells and, through the bystander effect, induce the cells to repair themselves .

Dr. Maddalena Mastrogiacomo of the University of Genoa in Italy is investigating new ways of growing bone tissue from bone marrow stem cells, by using novel mineral scaffolds. When the porous scaffold, based on calcium phosphate, is seeded with the cells, the cells differentiate into bone cells and permeate the scaffold, gradually absorbing the mineral so that eventually the entire structure consists solely of new bone .

Professor Giulio Cossu of the San Raffaele Hospital in Milan described how certain cells called mesangioblasts have the ability to cross the walls of blood vessels and then differentiate into muscle tissue. This is significant because in muscle-wasting diseases there is so much muscle to replace that it would be extremely difficult to inject new cells into every affected area. Professor Cossu’s team has taken mesangioblast cells from dogs that have muscular dystrophy, used genetic engineering to correct the defect responsible for the disease, then administered the engineered cells to the dogs. The treatment produced significant alleviation of the symptoms .

As well as working directly on models of human diseases, many researchers around the world are experimenting with fundamental but vital aspects of stem cell biology to assemble the appropriate tools to allow research to proceed efficiently. A striking example of this was presented by Professor Joseph Itskovitz-Eldor, of the Rabam Medical Centre in Haifa, Israel.

“To fulfil the promise that stem cell therapy offers, an unlimited supply of cells cultured in completely defined and controlled conditions is required,” Professor Itskovitz-Eldor said. Conventionally, stem cells are grown on flat plates, but the Israeli researchers have devised a way of growing the cells in suspension in a three-dimensional culture. “We can switch from three-dimensional to two-dimensional culture and the cells will still grow nicely,” Professor Joseph Itskovitz-Eldor said. “Experiments have shown that the cells retain their viability and integrity, and we think we can have unlimited numbers of undifferentiated human embryonic stem cells in defined conditions.”

Balanced against the advances in research, some problems stubbornly persist. In particular scientists would like to develop embryonic stem cell lines derived from large animals such as the pig, sheep, horse and cow.

As Professor Cesare Galli, a EuroSTELLS researcher in the Laboratory for Reproductive Technology in Cremona, Italy, explained, “Large animal models will provide models that are closer to the human than the rodent models we currently have. However, bona fide stem cells in large animals are still elusive and we have not got the right conditions to keep them going.”

Dr. Irena Vacková, of the Institute for Animal Science in Prague, has been attempting to develop an embryonic stem cell line from the pig. “The pig is a very good animal model for humans because it is physiologically and immunologically similar,” she said. “But it has proved impossible so far to establish a stable line of porcine embryonic stem cells.”

The overall picture of stem cell research was best summarised by Professor Inder Verma of the Salk Institute in the US, who said, “There must be a certain degree of caution in the way we portray these technologies. I believe the technology really is there, and there is a lot of exciting potential. We are making improvements – although we still need to know a lot about the way that these cells are regulated in the body and about any immunological consequences. There has been substantial progress over the last 20 years, but it is important to bear in mind that these things take time. As successful as these technologies may become there is still a long way to go.”

EuroSTELLS is the European Collaborative Research (EUROCORES) programme on “Development of a Stem Cell Tool Box” run by the European Medical Research Councils (MED (formerly EMRC)) Unit in the European Science Foundation. ESF provides scientific coordination and support for the networking activities of funded scientists through the EC FP6 Programme, under contract no. ERAS-CT-2003-980409. Research funding is provided by the participating national organisations.

Article 2 (released 17 October 2007)

New stem cells by reprogramming

By ‘de-programming’ existing specialised cells it might be possible to create cells which resemble embryonic stem cells, bypassing many of the ethical and moral objections to using human embryos. Researchers are discovering new ways to help ‘de-program’ specialised cells so that they can be re-programmed to form a range of different types of tissue, an international meeting of stem cell biologists was told. If this approach can be made to succeed, it could circumvent many of the ethical and moral objections that have been raised to using human stem cells derived from embryos – the ‘blank’ cells (‘toti- or ‘pluripotent’) that have the potential to turn, or differentiate, into multiple types of specialised cell and which could be used to treat many diseases where cells are not functioning correctly.

Professor Keith Campbell of the University of Nottingham in the UK presented new findings on cell de-programming to an international meeting in Milan (30 Sep – 2 Oct, “Challenges in Stem Cell Differentiation and Transplantation”) organised by the European Science Foundation’s EuroSTELLS stem cell programme and one of ESF’s Member Organisations, the National Research Council (CNR) of Italy.

Embryonic stem cell therapy relies on the fact that in the early stages of the development of the embryo, cells retain the ability to differentiate into every type of cell in the body. In theory an embryonic stem cell could be coaxed to grow into a liver cell or pancreatic cell, for example, and therefore could be used to repair or replace diseased or damaged tissue.

However, many hurdles remain to be cleared, both scientific and ethical. Professor Campbell, who works as part of a EuroSTELLS consortium, told the Milan meeting, “There are many challenges associated with using embryonic cells. Furthermore if the entire population were to be served by the sorts of treatments envisaged, we would need huge numbers of embryonic cell lines in order to cover the wide range of immunological types present in the population to prevent or reduce rejection.”

One possible way around these problems is to produce ‘personalised’ cell populations. This approach would entail removing cells from an individual that have already differentiated and de-program them so that they revert from being specialised cells to becoming ‘blank’ cells, similar to embryonic stem cells. They could then be re-programmed into a new type of cell and transplanted back into the person donating the cells, therefore preventing rejection.

The key to this approach is to repackage the cell’s genetic material. When a stem cell differentiates into a specialised cell, the genetic code – the sequence of genes on the DNA contained within the chromosomes – remains the same. What alters is the way that the DNA is packaged. Various ‘epigenetic’ modifications take place, in which the DNA is folded and twisted, and with certain molecules bolted onto it which have the effect of exposing some regions of the DNA and masking others, ultimately have an effect on how the genetic code is expressed. De-programming would require the genetic material to be unpacked, reverting to its original state before the cell became differentiated.
Such de-programming is feasible – the creation of cloned animals such as Dolly the sheep is achieved by a process called somatic cell nuclear transfer (SCNT), in which the nucleus of a differentiated adult cell is removed and placed into an unfertilised egg cell, termed an oocyte, whose own genetic material has been extracted. Various biochemical factors within the egg cell’s contents – its cytoplasm – somehow unravel and ‘clean up’ the DNA contained within the transferred nucleus, making it equivalent to an embryonic stem cell, which can then divide and proliferate and form all the other types of cell needed to make a new organism.

“What causes this kind of reprogramming? We do not know,” said Professor Campbell. “But it is clear that it involves some factors within the cytoplasm of the egg cell.”

The entire process of transferring a nucleus from one cell into another cell is fraught with potential pitfalls, and Professor Campbell’s team has been working on ways to improve the success rate of SCNT.

For example when the nucleus is removed from the oocyte, inevitably some of the cell’s cytoplasm is also extracted. The Nottingham researchers have been analysing the proteins that are removed inadvertently to see if these might be important in de-programming the introduced genetic material.

The team has also shown that de-programming of the somatic cell nucleus can be improved if caffeine is present in the cytoplasm of the oocyte. This appears to have a key effect on two enzymes called kinases that possibly helps to open up the donated nuclear material, exposing it to the important de-programming factors present in the oocyte cytoplasm.

Another approach that the Nottingham researchers have adopted is to expose the donor cells to the oocyte cytoplasm before the transfer occurs. “It is clear that protein molecules within the oocyte cytoplasm can deprogram the genome, so we are asking if it is possible to use the protein from an egg directly on the cell whose nucleus is to be transferred,” Professor Campbell said. The team has shown with eggs from amphibians that it is indeed possible to invoke a range of epigenetic changes in the nucleus of the donor cells which, said Professor Campbell, “push the epigenetic profile towards that of the stem cell.”

Professor Campbell said, “Ultimately this work is aimed at investigating whether we can bypass the need for a human embryo. If we can take a differentiated cell and drag it back to the state it was in the embryo then we could solve a lot of the current problems.”

See the following papers for more information on reprogramming:

Yang X., et al. Nuclear reprogramming of cloned embryos and its implications for therapeutic cloning. Nature Genetics, 2007, Mar 39(3), 295-302.

Alberio R., et al. Reprogramming somatic cells into stem cells. Reproduction, 2006, Nov 132(5), 709-20.

Armstrong L., et al. Epigenetic modification is central to genome reprogramming in somatic cell nuclear transfer. Stem Cells, 2006, Apr 24(4), 805-14.

Media Coverage

Article 3 (released 22 October 2007)

An eye for an eye: using stem cells to treat damaged eyes and a rare skin disorder

Stem cells can be used to grow new corneal tissue and, together with gene therapy, treat a rare genetic skin disorder. Doctors and scientists in Italy have shown how stem cells can be used to treat damaged eyes and, in combination with gene therapy, a rare and debilitating skin disease.

Professor Michele De Luca of the University of Modena and Reggio Emilia described the work to an international meeting of stem cell scientists in Milan (30 Sep – 2 Oct, “Challenges in Stem Cell Differentiation and Transplantation”) organised by the European Science Foundation’s EuroSTELLS stem cell programme in conjunction with the National Research Council of Italy.

Stem cell therapy involves the use of stem cells – ‘blank’ cells (‘toti- or ‘pluripotent’) that have not differentiated into specialised cells – to generate new tissues or organs. While widespread stem cell therapy lies some way in the future, Professor De Luca pointed out that it has been used already for many years in the treatment of burns. Many tissues of the body are continuously regenerated by their own population of stem cells. In the skin, such cells are called holoclones and for decades doctors have taken small samples of these cells from burns patients and cultured the cells into new skin that can be grafted onto the wound.

Professor De Luca’s team showed that cells of the transparent outer covering of the eye, the cornea, are constantly being replaced by new cells deriving from an area surrounding the cornea called the limbus. The cells differentiate into corneal epithelium and migrate to the cornea.

“If the cornea is damaged severely by a chemical burn or infection, for example, it can become opaque and necessitates a transplant,” Professor De Luca told the meeting. “However, a transplant will only be successful if the patient’s limbus has remained intact so that it can continue to replenish the new cornea.”

For many years doctors did not understand why some transplants failed – because they did not appreciate the requirement for the limbus.

In cases where the limbus is destroyed there has been little hope to restore the patient’s sight. Professor De Luca’s team decided to take a leaf from the way that burns are treated and grow a new cornea from limbar stem cells taken from the healthy eye.

By removing a small sample of these cells it was possible to culture a new cornea and graft it on to the damaged eye. The team showed that of 240 patients who were operated on in this way, the cornea regenerated successfully in 70% of cases.

The researchers then turned their attention to a rare but debilitating genetic disease of the skin resulting in a syndrome known as Epidermolysis Bullosa, in which the skin is highly fragile and prone to blistering due to faulty proteins that effectively anchor the surface layers of skin to the body.

In one form of the disease there is a mutation in one of these anchoring proteins called laminin 5. The Italian researchers obtained consent to carry out a small-scale trial of a novel gene therapy using skin holoclones on one patient, a 37-year-old male, on small part of his body .

“Because the patient’s body was so badly affected it was difficult to isolate any stem cells from his skin,” Professor De Luca told the conference. “Most people have between seven and ten per cent of holoclones. Our man had none. Eventually we found a few in the palms of his hand and cultured them from a biopsy.”

The team then used gene therapy to insert the correct laminin gene into the growing cells and grafted the new tissue onto the patient’s body. The graft was successful and after several months the skin remained to all intents normal, without the blistering and flaking.

“This demonstrates that it is possible to use stem cells in gene therapy for genetic skin disorders,” Professor De Luca said.

Last Updated January 2008