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Stem cell models of nervous system diseases

April 8, 2013

Neurons generated from human induced pluripotent stem cells (iPSCs). Human skin cells were reprogrammed to make iPSCs by introducing defined genetic factors. Credit: Rakesh Karmacharya, Wellcome Images

Neurological conditions such as Alzheimer’s Disease, Parkinson’s Disease and pain come at a huge cost to society and the economy, and one of the big challenges of modern neuroscience is to develop effective treatments for them. Recent years have seen big leaps in our understanding of these conditions, but effective treatments are still a long way off.

Embryonic stem cells offered the hope of treatment for these and many other brain diseases, but their use is fraught with ethical problems. Six or seven years ago, researchers discovered that they could coax mature cells taken from the human body to revert to a stem cell-like state, and then reprogram them to generate virtually any cell type. The discovery led to the Nobel Prize in Medicine, and these so-called induced pluripotent stem cells (iPSCs) have become a very hot topic of research.

Researchers quickly realised that iPSCs have huge potential for understanding and treating neurological diseases. Within several years of the initial discovery, they found that they can take skin cells from patients and reprogram them into neurons, and more recently they have discovered that they can by-pass the intermediate stage altogether, to make cells switch from one type directly to another.

Researchers working in this area reported on their progress today in a symposium at the BNA Festival of Neuroscience.

James Bilsand of the Pfizer Neusentis Pharmaceutical Research Unit in Cambridge is using iPSCs to study how pain is transmitted from the body to the brain. This is carried out by a specialised subset of primary sensory neurons called nociceptors, which detect damaging stimuli – certain chemicals, excessive pressure, and hot and cold temperatures – and transmit signals about them into the spinal cord, where they form connections with secondary sensory neurons, which relay the signals up to the brain.

During development, nociceptors are produced from a population of migrating cells called the neural crest, which are present temporarily in the embryo. This requires molecular signals that activate a unique combination of genes that give nociceptors their characteristic properties. The molecules involved have been identified, so researchers can now use them to convert iPSCs into nociceptors.

Bilsand and his colleagues have developed a method of creating iPSCs from blood samples and then reprogramming them into nociceptors, and have found that the reprogrammed cells resemble nociceptors very closely, expressing most of the genes that give the cells their distinct electrical properties. They are now using cells from patients carrying genetic mutations that cause insensitivity to pain, or conditions such as erythromelalgia, which is characterised by severe burning pain in the arms and legs, to learn more about them.

Using a similar approach, Rick Livesey of the Gurdon Institute at the University of Cambridge and his colleagues have developed methods to produce neurons from iPSCs derived from patients with Down Syndrome, who invariably go on to develop Alzheimer’s at a young age. They have recently extended the approach to work with cells from patients with inherited forms of Alzheimer’s Disease, which account for approximately 1% of cases.

Alzheimer’s, like all other neurodegenerative diseases, is characterised by misfolded proteins that build-up to form insoluble clumps in the brain. Livesey and his colleagues have found that neurons produced from the iPSCs of both Down’s and Alzheimer’s patients appear to recapitulate this, developing the plaques and tangles, the pathological hallmarks of the disease. They also form functioning networks when grown in a Petri dish, and this may enable the researchers to better understand how the rogue proteins transfer from one cell to another and destroy synaptic connections.

Tilo Kunath of the MRC Centre for Regenerative Medicine at the University of Edinburgh and his colleagues have used iPSCs from a patient with Parkinson’s Disease to create a number of different cell lines. As well as creating the dopamine-producing midbrain neurons that die in Parkinson’s, they have also created the cerebral cortical neurons that degenerate in Dementia with Lewy bodies, and the motor neurons in the brain and spinal in a condition called multiple system atrophy.

All three conditions are related, and are associated with a protein called alpha-synuclein. Kunath’s group has found that their cell lines produce extremely high levels of the protein, are investigating how it exerts its toxic effect on cells.

As well as enabling researchers to learn more about the cellular mechanisms underlying the start and progression of these diseases, they are also very useful to screening potential new drug treatments. Eventually, they may also prove to be useful for the development of cell transplantation not only for diseases such as Alzheimer’s but also other neurological conditions such as stroke.


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