Neural stem cells for spinal cord repair

Sandner B, Prang P, Rivera FJ, Aigner L, Blesch A, Weidner N.

Source

Spinal Cord Injury Center, Heidelberg University Hospital, Schlierbacher Landstrasse 200a, 69121, Heidelberg, Germany.

Spinal cord injury (SCI) causes the irreversible loss of spinal cord parenchyma including astroglia, oligodendroglia and neurons. In particular, severe injuries can lead to an almost complete neural cell loss at the lesion site and structural and functional recovery might only be accomplished by appropriate cell and tissue replacement. Stem cells have the capacity to differentiate into all relevant neural cell types necessary to replace degenerated spinal cord tissue and can now be obtained from virtually any stage of development. Within the last two decades, many in vivo studies in small animal models of SCI have demonstrated that stem cell transplantation can promote morphological and, in some cases, functional recovery via various mechanisms including remyelination, axon growth and regeneration, or neuronal replacement. However, only two well-documented neural-stem-cell-based transplantation strategies have moved to phase I clinical trials to date. This review aims to provide an overview about the current status of preclinical and clinical neural stem cell transplantation and discusses future perspectives in the field.

p53 Regulates Cell Cycle and MicroRNAs to Promote Differentiation of Human Embryonic Stem Cells

Jain AK, Allton K, Iacovino M, Mahen E, Milczarek RJ, Zwaka TP, Kyba M, Barton MC.

Source

Program in Genes and Development, Center for Stem Cell and Development Biology, Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.

Multiple studies show that tumor suppressor p53 is a barrier to dedifferentiation; whether this is strictly due to repression of proliferation remains a subject of debate. Here, we show that p53 plays an active role in promoting differentiation of human embryonic stem cells (hESCs) and opposing self-renewal by regulation of specific target genes and microRNAs. In contrast to mouse embryonic stem cells, p53 in hESCs is maintained at low levels in the nucleus, albeit in a deacetylated, inactive state. In response to retinoic acid, CBP/p300 acetylates p53 at lysine 373, which leads to dissociation from E3-ubiquitin ligases HDM2 and TRIM24. Stabilized p53 binds CDKN1A to establish a G(1) phase of cellcycle without activation of cell death pathways. In parallel, p53 activates expression of miR-34a and miR-145, which in turn repress stem cellfactors OCT4, KLF4, LIN28A, and SOX2 and prevent backsliding to pluripotency. Induction of p53 levels is a key step: RNA-interference-mediated knockdown of p53 delays differentiation, whereas depletion of negative regulators of p53 or ectopic expression of p53 yields spontaneous differentiation of hESCs, independently of retinoic acid. Ectopic expression of p53R175H, a mutated form of p53 that does not bind DNA or regulate transcription, failed to induce differentiation. These studies underscore the importance of a p53-regulated network in determining the human stem cell state.

A Step-up Approach for Cell Therapy in Stroke: Translational Hurdles of Bone Marrow-Derived Stem Cells

Glover LE, Tajiri N, Weinbren NL, Ishikawa H, Shinozuka K, Kaneko Y, Watterson DM, Borlongan CV.

Abstract

Stroke remains a significant unmet condition in the USA and throughout the world. To date, only approximately 3% of the population suffering an ischemic stroke benefit from the thrombolytic drug tissue plasminogen activator, largely due to the drug's narrow therapeutic window. The last decade has witnessed extensive laboratory studies suggesting the therapeutic potential of cell-based therapy for stroke. Limited clinical trials ofcell therapy in stroke patients are currently being pursued. Bone marrow-derived stem cells are an attractive, novel transplantable cell source for stroke. There remain many unanswered questions in the laboratory before cell therapy can be optimized for transplantation in the clinical setting. Here, we discuss the various translational hurdles encountered in bringing cell therapy from the laboratory to the clinic, using stem celltherapeutics as an emerging paradigm for stroke as a guiding principle. In particular, we focus on the preclinical studies of cell transplantation in experimental stroke with emphasis on a better understanding of mechanisms of action in an effort to optimize efficacy and to build a safety profile for advancing cell therapy to the clinic. A forward looking strategy of combination therapy involving stem cell transplantation and pharmacologic treatment is also discussed.

Production of zebrafish offspring from cultured spermatogonial stem cells

1. Toshihiro Kawasaki,
2. Kenji Saito,
3. Chiharu Sakai,
4. Minori Shinya,
5. Noriyoshi Sakai

Germ-line stem cells have the potential to be a very powerful tool for modifying the genetic information of individual animals. As a first step to use spermatogonial stem cells (SSCs) to enable genetic modification, we here describe effective long-term culture conditions for propagating zebrafish SSCs and for the production of offspring from these cultured SSCs after their differentiation into sperm in transplanted testicular cell aggregates. Dissociated testicular cells were cultured in specific medium with some modified supplements, including several mammalian growth factors. The spermatogonia actively proliferated and retained the expression of exogenous green fluorescent protein under the control of vas and sox17 promoters and also of promyelocytic leukemia zinc finger (Plzf), a marker of undifferentiated spermatogonia, after 1 month in culture. This is a longer period than the entire natural spermatogenic cycle (from SSCs to sperm). The use of subcutaneously grafted aggregates of these cultured spermatogonia and freshly dissociated testicular cells showed that these SSCs could undergo self-renewal and differentiation into sperm. Artificial insemination of these grafted aggregates successfully produced offspring. This culture method will facilitate the identification of new factors for the maintenance of SSCs and enable the future enrichment of genetically modified SSCs that will produce offspring in zebrafish.

What's all this about stem cells?

by Tom Shakespeare

America is trialling it, Barack Obama is about to endorse it, Scottish doctors think it could cure a form of blindness, and a toddler is going all the way to China for it. Over the last month, it's been hard to miss all the news stories about stem cell therapy. We know that therapies based on stem cells are likely to be extremely beneficial to all sorts of disabled people in the future, but where are we with it all right now? I think it's time for a bit of a recap ...

What is stem cell therapy?

Stem cells are undifferentiated cells - lacking qualities that make them different or unique - which are capable of developing into any of the 200 different types of cell in the human body. They are derived from embryos, from the umbilical cord or, with greater difficulty, from the scarce stem cells in adults or children.

Stem cells can be used to grow tissues for transplantation - for example, heart muscle or brain cells or liver cells. They can also be used as models for disease, which can then be used in research - meaning better knowledge or less reliance on animal experimentation. This has recently been achieved for spinal muscular atrophy.

Who might be helped by these therapies?

People who have diseases or impairments which are caused by tissue damage or degeneration can potentially be helped by stem cell therapy. For example, people with diabetes, liver disease and Parkinson's, maybe even people with spinal cord injury.

A new trial is ex

ploring whether stroke survivors could benefit too, whilst the latest news suggests that stem cells from patients' own bone marrow could help reverse the early signs of MS.

Most of these therapies are only at the stage of initial trials in humans - for example, studies on corneal blindness and spinal cord injury are just starting.Does it work?Stem cell treatments have been successful in treating Severe Combined Immune Deficiency (SCID) a

nd a few other conditions in research settings. While stem cell therapy sounds good in theory, in practice it is very hard to grow specific cell types and control their growth safely. The children cured of SCID went on to contract a form of leukaemia. Research continues to understand why, and to improve safety and effectiveness.

When might therapies be available?

The first clinical trial of an embryonic stem cell therapy has just been authorised by the US Food and Drug Administration.

Clinical trials can take up to 10 years, so even if a therapy is shown to be successful, scientists or pharmaceutical companies then have to prove that it is safe. Animal trials have shown that therapies for spinal cord injury, muscular dystrophy and other conditions have great potential, but effective treatments are still a long way off. Therapies may be beneficial in the early days after a spinal cord injury, but not benefit those who have been injured for a long time.

What's the ethical issue here?

Embryonic stem cell therapy depends on destroying embryos - usually surplus embryos from IVF treatment. Those who believe that life starts at conception will equate this to murder. The Vatican reaffirmed its opposition to embryonic stem cell research in December, but permits research using adult stem cells.

Another controversy is over somatic cell nuclear transfer, otherwise known as therapeutic cloning, which would enable stem cell tissues to be matched to the patient, but bring us closer to the possibility of reproductive cloning.

Under President Bush, creation of new embryonic stem cell lines was forbidden in America. President Obama is expected to permit a more liberal approach to research.

What's the political issue?

For those who take a pure social model approach to disability, the problem for disabled people is not their impairment but the barriers and discrimination within society. Stem cell therapy is offered as a cure for disability, whereas activists often deny their need or desire for cure.

Moreover, promises of scientific breakthroughs and wonderful medical treatments have been made for over fifty years, and there is scepticism about the current stem cell hyperbole. Superman actor Christopher Reeve was so convinced that stem cell therapy would cure spinal cord injury that he said that barrier removal and disability rights was unnecessary. Most others disagree.

So is it just a load of hype?

There is definitely lots of media excitement about stem cell therapy, as well as the occasional irresponsible announcement from a scientist. There are also big commercial interests involved: stories of miraculous stem cell treatments in less regulated countries such as China, Thailand, India and Russia are questionable, with vulnerable consumers being charged an average of 21,500 dollars for unproven therapies.

In Britain, many parents have been encouraged to pay for their infant's umbilical cord blood to be stored in private stem cell banks, with the hope that this might help with future disease. But scientists are sceptical as to whether the promised benefits will materialise.

But despite these negative stories, overall it is fair to say that leading scientists in the UK and US are responsible and very tightly regulated, and that many believe that ultimately this line of research will transform medicine.

You'll see many more news stories in the months and years ahead, so stay tuned for more updates on 'tailor made tissues'.

BBC Videos on Stem Cells

• BBC - Learning Zone Class Clips - Stem cell research and medicine - Science Video

  … and medicine Key Info Stem cell research and medicine Duration: 04:50 What is stem cell research and how can stem cells be used in medicine? A…

• BBC - Learning Zone Class Clips - Stem cell research and medicine - Science Video

  … and medicine Key Info Stem cell research and medicine Duration: 04:50 What is stem cell research and how can stem cells be used in medicine? A…

• BBC - Learning Zone Class Clips - Ethics of using foetal stem cells for stroke treatment - Science Video

  Sinden, Chief Scientific Officer of ReNeuron, a clincal-stage stem cell business. Dr Sinden explains the ethics of using stem cells from an aborted…

Chemical in bad breath 'influences' dental stem cells

Hydrogen sulphide, the gas famed for generating the stench in stink bombs, flatulence and bad breath, has been harnessed by stem cell researchers in Japan.

Their study, in the Journal of Breath Research, investigated using it to help convert stem cells from human teeth into liver cells.

The scientists claimed the gas increased the purity of the stem cells.

Small amounts of hydrogen sulphide are made by the body.

It is also produced by bacteria and is toxic in large quantities.

Therapy

A group in China has already reported using the gas to enhance the survival of mesenchymal stem cells taken from the bone marrow of rats.

Researchers at the Nippon Dental University were investigating stem cells from dental pulp - the bit in the middle of the tooth.

They said using the gas increased the proportion of stem cells which were converted to liver cells when used alongside other chemicals. The idea is that liver cells produced from stem cells could be used to repair the organ if it was damaged.

Dr Ken Yaegaki, from Nippon Dental University in Japan, said: "High purity means there are less 'wrong cells' that are being differentiated to other tissues, or remaining as stem cells."

One of the concerns with dental pulp as a source of stem cells is the number that can be harvested.

However, the study did not say how many cells were actually produced.

Prof Chris Mason, a specialist in regenerative medicine at University College London, said: "It would be interesting to see how hydrogen sulphide works with other cells types."