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Adult versus Embryonic Stem Cells

Dr. Mae-Wan Ho gives the latest score-sheet in the great stem cell debate.

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In June, the journal Nature published two articles online, one describing the use of embryonic stem (ES) cells to reverse the symptoms of Parkinson’s disease, the other, the isolation of adult stems cells from bone marrow that can produce all cell types in the body.

The accompanying news report entitled, "Stem cell hopes double", was obviously intended as input to the US Senate debate over the cloning of human embryos for medical research, which has stalled the week before. It came down firmly on the fence: "Today’s papers do not settle the adult-versus-embryo dispute: they suggest that both could yield promising therapies. Different cell types might best treat different diseases, so most scientists advocate supporting both types of research."

But this judgement not only brushes ethical considerations aside, it misrepresents the science and lacks consideration of good therapeutic practice.

Parkinson’s disease is associated with the loss of midbrain neurones that make dopamine, a neurotransmitter (molecule that transmits signals between nerve cells). The research team headed by Ron McKay of the National Institute of Neurological Disorder and Stroke (National Institute of Health, Bethesda, Maryland) created a highly enriched population of midbrain stem cells that differentiated into dopamine-producing neurones with electro-physiological and behavioural properties expected of neurones from the midbrain.

In order to make those neurones, the ES cells were transformed with a rat gene coding for nuclear receptor related -1 (Nurr1) transcription factor, driven by a Cytomegalovirus promoter to make the gene over-express. Nurr1 is known to have a role in the differentiation of midbrain precursor cells into dopamine neurones. The ES cells were then subjected to an elaborate 5-stage culture procedure. The resulting cells expressed many molecular, morphological and functional features specific for midbrain dopamine-neurons. And the dopamine released on depolarization (electrical stimulation) of the cells was markedly higher in the cultures of stage 5 Nurr1 ES cells compared with unmodified ES cells.

In rodents, administration of 6-hydroxy dopamine in the midbrain kills dopamine neurons, providing a model of Parkinson’s disease. These animals then either received a sham operation or a graft of 5 x 105 Nurr1 ES cells, or unmodified ES cells. At 4 and 8 weeks after grafting, the animals were sacrificed and their brains examined. No dopamine-producing midbrain neurones developed in the sham-operated animals. Animals grafted with Nurr1 ES cells showed dopamine-producing cells with complex morphologies. There was no sign of cell division of the engrafted cells. But their processes were found in the brain of the host up to 2mm from the graft. The cells were tested electro-physiologically up to 140days after grafting and found to express the characteristics of dopamine-producing mid-brain neurones.

While the sham-operated animals showed no improvement in neurological performance, animals grafted with unmodified ES cells recovered slightly, and Nurr1 ES engrafted animals showed the best recovery. Another reassuring result was that no teratomas were found in the grafted animals.

On the adult stem cells front, the research group headed by Catherine Verfaille in the Departments of Medicine, Microbiology, Neurosurgery and Genetics, Cell Biology and Development of the University of Minnesota Medical School, Minneapolis, discovered a rare kind of cells within the human bone marrow- the multipotent adult progenitor cells (MAPCs) that can be expanded for more than 80 population doublings. The cells can be made to differentiate, at the single cell level, into bone and cartilage cells, skeletal muscle cells, fat cells, bone marrow stroma (ground substance) and endothelial cells (internal linings) of the internal organs.

Similar cells capable of differentiating in vitro into cells of all three germ layers can be selected from mice (m) and rat (r) bone marrow. The mMAPCs have been expanded in culture for more than 120 doublings, and the rMACPCs for more than 100 doublings.

When injected into an early blastocyst mouse embryo, single MAPCs can contribute to most, if not all somatic cell types. On transplanting into a non-irradiated host, MAPCs engraft and differentiate into haematopoietic cells, in addition to the epithelium of liver, lung and gut. Engraftment in haematopoeitc system as well as the gastrointestinal tract is increased when MAPCs are transplanted in a minimally irradiated host.

These cells show a high level of genomic stability under culture conditions, with all except one population retaining the normal chromosome complement after many population doublings. When grown to confluency, they stopped proliferating and when cultured in serum-free medium, and differentiation-inducing cytokines, after 40 or more than 120 population doublings, growth arrest and terminal differentiation was seen. There was also no tumour-formation on transplantation.

So, how do ES and adult stem cells score at this point?

These latest results show that the ES cells need to be genetically modified and extensive manipulation in vitro before they can be transplanted safely. Direct transplant of ES cells are known to give rise to teratomas and uncontrollable cell proliferation. There is already evidence that ES cells are genetically unstable in long term culture, and are especially prone to chromosomal abnormalities. The risks involved in using the cytomegalovirus promoter to drive over-expression of the transcription factor are undetermined. To avoid immune rejection, the ES cells have to be tissue-matched from a bank of stem cells created from ‘spare’ human embryos. Otherwise, a special human embryo has to be created for the purpose, by transferring the patient’s genetic material into an empty egg, a procedure prone to failure and morally objectionable to many, including scientists.

By contrast, adult stem cells could be transplanted directly without genetic modification or pre-treatments. They simply differentiate according to cues from the surrounding tissues and do not give uncontrollable growth or tumours. The adult stem cells also show high degrees of genomic stability during culture. There is no problem with immune rejection because the cells can readily be isolated from the patients requiring transplant. And there is no moral objection involved. Better yet, research can be directed towards encouraging adult stem cells to regenerate and repair damaged tissues in situ, without the need for cell isolation and in vitro expansion. By minimising intervention, risks are reduced, as well as cost, making the treatment available to everyone and not just the rich.

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