Scientists at The Scripps Research Institute and the Burnham Institute for Medical Research have just completed a large-scale comparative phosphoproteomic analysis of human embryonic stem cells (hESCs). The accomplishment is the first of its kind and also includes a detailed analysis of differentiated derivatives of hESCs. Data from the study may ultimately allow for greater control over the molecular mechanisms that determine whether or not stem cells differentiate into more specialized cells, or merely divide without differentiating.

Protein phosphorylation, a biochemical process which is essential for cell signaling, involves the modification of protein activity via the addition of a phosphate molecule. It is one of the most widely studied aspects of protein modification and commonly employed as a fundamental tool of proteomics. A logical extension of "genomics", proteomics is defined as the large-scale study of proteins, and in particular of the mechanisms by which the 3-dimensional structure of any particular protein influences biochemical function and activity. Similar to the concept of a genome, the "proteome" consists of the entire complement of proteins which any particular biological system or organism produces.

Combining both areas of specialization, the scientists in the current study used methods of "phosphoproteomic" analysis to catalogue 2,546 phosphorylation sites on 1,602 phosphoproteins, the identification of which has now shed new light on signaling pathways. Follow-up experiments further confirmed specific phosphoproteins and cell pathways that the researchers had identified using the phosphoproteomic data as a predictive tool in target samples. Among other findings, the scientists observed the various roles that phosphorylation plays in determining cell fate, especially in the phosphorylation of various kinases as well as specific transcription regulators such as epigenetic and transcription factors. In particular, proteins that are involved in the JNK (Jun N-terminal kinase) signaling transduction pathway were observed to be phosphorylated in undifferentiated hESCs, a finding which would suggest that JNK signaling inhibition may be involved in cell differentiation, as independently confirmed by other hESC studies. Additionally, phosphoproteins involved in the RTK (receptor tyrosine kinase) signaling pathways were found to be especially numerous in undifferentiated hESCs, and follow-up studies demonstrated that multiple RTKs can maintain hESCs in an undifferentiated state.

According to Dr. Laurence Brill, a member of the team of researchers who conducted the study, "This research will be a big boost for stem cell scientists. The protein phosphorylation sites identified in this study are freely available to the broader research community, and researchers can use these data to study the cells in greater depth and determine how phosphorylation events determine a cell’s fate."

Prior to this particular study, protein phosphorylation was poorly understood in hESCs, and even though the process is still not yet fully elucidated, the study nevertheless demonstrates the utility of phosphoproteomic data as a predictive and analytic tool in the determination of cell fate, at least within hESCs. Extrapolation to mechanisms of differentiation and cell fate in adult stem cells should prove to be of even greater and more immediate clinical utility, however, since adult stem cells are already being used in the treatment of a wide variety of diseases and injuries, unlike hESCs, which have yet to advance beyond the experimental laboratory stage.

Along with Dr. Laurence Brill, the team of scientists who conducted the study also include Drs. Sheng Ding and Evan Y. Snyder.

The biotechnology giant Genzyme Corporation announced today that it has received regulatory approval from the European Commission for the commercial marketing of one of its products, Mozobil. A proprietary, injectable formulation of plerixa, Mozobil stimulates the mobilization and migration of the body’s own adult, hematopoietic stem cells out of the bone marrow and into the peripheral blood where the cells can be easily collected. The intended, initial use of Mozobil in the European market is for patients with lymphoma and multiple myeloma who require an autologous (in which the donor and recipient are the same person) adult stem cell transplant, but who are suspected of having inadequate mobilzation and who have previously failed conventional treatment.

According to Dr. Mohamad Mohty of the Stem Cell Transplant Program at the University Hospital in Nantes, France, Mozobil "has the potential to transform the field of stem cell transplantation. This new treatment will allow more patients with yet incurable malignancies to confidently move on to a potentially life-saving autologous stem cell transplant."

Mozobil has been evaluated in two randomized, double-blind, placebo controlled Phase III clinical trials as a treatment for patients with non-Hodgkin’s lymphoma and multiple myeloma. In addition to Mozobil, the patients were also given G-CSF (granulocyte-colony stimulating factor), a combination which proved to increase stem cell mobilization yield as well as graft durability rates as revealed in year-long follow-up data. Additionally, Mozobil has already been tested on more than 1,000 patients in Europe over the past year who received the treatment through "compassionate use" programs. Because it was formulated to treat specific medical conditions, Mozobil has been granted "orphan drug" status both in the United States and the European Union.

As a new option for a broad group of cancer patients, Mozobil offers distinct economic as well as clinical benefits. Since it has been found to decrease the number of days required for apheresis, Mozobil reduceds the need for a second mobilization procedure, thereby reducing the overall cost of the medical treatment. A minimum of approximately two million hematopoietic stem cells per kilogram of body weight must be collected before any patient can receive an autologous adult stem cell transplant, although twice that many stem cells would allow for a more effective outcome. Without Mozobil, many patients are unable to produce enough stem cells, even in multiple collection procedures that are performed over multiple days, in which case such patients are not allowed to proceed with the therapy. With Mozobil, however, most patients are able to produce an adequate amount of stem cells during the first collection procedure, and are therefore able to complete the entire transplant therapy in a more timely and efficient manner.

According to Paula Soteropoulos, Genzyme vice president and general manager of Mozobil, "There is strong interest among European physicians for Mozobil. With today’s approval, we will move quickly to make this important product broadly available to the transplant community."

Approximately 55,000 hematopoietic stem cell transplants are performed each year throughout the world for Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, multiple myeloma and related disorders. Mozobil was approved for use in the U.S. in December of 2008, and in Mexico in May of 2009. In addition to the E.U., Genzyme has also filed applications for the approval of Mozobil in Argentina, Australia, Brazil, Israel and Singapore, with additional applications for other countries still in the planning stage. Global peak sales of Mozobil are projected to reach $400 million annually.

As the world’s third-largest biotechnology company, Genzyme currently employs more than 11,000 people around the world, in approximately 80 offices and laboratories that are located in 40 countries. In 2008, Genzyme reported $4.6 billion in global revenue from more than 25 products that are available throughout the world.

Scientists at the Research Institute of Science and Technology at the Tokyo University of Science have announced the successful creation of a "tooth germ" from which an entire mouse tooth has been grown in vivo. The accomplishment is believed to have far-reaching implications and applications to a number of medical specializations that include the replacement of entire organs.

In an article entitled, "Fully functional bioengineered tooth replacement as an organ replacement therapy", the scientists report that, "This study represents a substantial advance and emphasizes the potential for bioengineered organ replacement in future regenerative therapies."

Led by Dr. Takashi Tsuji and using a method which they had developed two years ago, the researchers used mouse embryonic stem cells to create a "bioengineered tooth germ" – a tiny "package" of cells, approximately 500-micrometers in length, containing all the genetic instructions for the formation of a tooth – which the scientists then implanted inside a mouse’s tooth socket from which a natural tooth had been removed. Approximately 5 weeks later, a new tooth erupted through the gum, and by 7 weeks the tooth was fully developed, complete with nerve fibers that were responsive to pain tests. The new tooth was found to exhibit all the properties of a natural tooth, with the one exception that it also appears to glow green when viewed under an ultraviolet light, since the scientists employed the common laboratory technique of tagging the genes with a green fluorescent protein in order to facilitate tracking of the genes. The process was then repeated in additional mice with identical results.

In 2007, using a similar proceedure the same team of researchers had been able to grow new teeth inside the bellies of mice, from which the teeth were then transferred to the jaws of mice. This new report, however, represents the first documented example of a bioengineered tooth that is fully functional because it has been completely grown in its natural habitat. In fact, the mice in whom the teeth were grown naturally responded to the presence of the new teeth by using them for the chewing of food.

As Dr. Kazuhisa Nakao, one of the authors of the study, explains, "Every bioengineered tooth erupted through the gum and had every tooth component such as dentine, enamel, pulp, blood vessels, nerve fibres, crown and root." According to Dr. Yasuhiro Ikeda of the Mayo Clinic in Rochester, Minnesota, such an accomplishment is "expected to evolve into a wide variety of organ-regenerative technologies for the liver, kidneys and other organs."

As the authors noted in their publication, "The bioengineered tooth, which was erupted and occluded, had the correct tooth structure, hardness of mineralized tissues for mastication, and response to noxious stimulations such as mechanical stress and pain in cooperation with other oral and maxillofacial tissues." As they further concluded, "The ultimate goal of regenerative therapy is to develop fully functioning bioengineered organs which work in cooperation with surrounding tissues to replace organs that were lost or damaged as a result of disease, injury, or aging. Here, we report a successful fully functioning tooth replacement in an adult mouse achieved through the transplantation of bioengineered tooth germ into the alveolar bone in the lost tooth region. We propose this technology as a model for future organ replacement therapies."

Earlier this month, British scientists at Newcastle University in England reported the creation of spermatozoa from human stem cells, the official announcement of which was published in the journal Stem Cells and Development. Today, however, the editor of the journal Nature has announced that the British scientists have decided to retract the article.

Although the editor of Stem Cells and Development, Graham Parker, initially announced on this journal’s website that the sperm study "is being retracted", without offering any explanation, it was the journal Nature which quoted him as having said that two paragraphs in the article’s introduction were found to have been plagiarized, and were taken from a 2007 review in the journal Biology of Reproduction.

The plagiarism is being attributed to a research associate who left the University, and the violation is not considered to be egregious enough to undermine the overall validity of the paper. Nevertheless, even though the authors assert that the underlying scientific integrity of the study remains uncompromised, a number of other scientists acknowledge that concerns might now be raised over the general credibilty of the study.

According to Allan Pacey, secretary for the British Fertility Society, "This is clearly scientific misconduct. I can understand why people might think, if they were sloppy here, maybe they were sloppy elsewhere." The claims made in the publication were highly controversial, and today’s retraction of the paper only adds further fuel to the controversy. As Pacey adds, "It was bad enough to begin with, and now we’ve got another scandal to deal with."

In an official statement issued to the press, representatives of Newcastle University assert that, "No questions have been raised about the science conducted or the conclusions of the research." Additionally, they add that the paper will now be resubmitted to another academic journal for publication, and that Newcastle University will be overseeing a more thorough supervision of research associates in the future.

According to Elizabeth Wager, however, chairperson of the international organization of publishers and editors known as the Committee on Publication Ethics, "This sets a line in the sand. Editors have a responsibility to correct the scientific record if misconduct has occurred."

Although plagiarism per se is not considered to be as serious an offense as data fabrication, nevertheless the incident evokes unpleasant memories among the global scientific community of the Hwang Woo-Suk scandal, whose two articles on human cloning that were published in the highly respected journal Science in 2004 and 2005 were later discovered to have been fraudulent.

Dr. Karim Nayernia, who led the spermatozoa research at Newcastle University, was unavailable for comment.

Scientists at the Fondazione Poliambulanza-Instituto Ospelaliero in Brescia, Italy have used placental adult stem cells in the treatment of fibrotic lung diseases in laboratory animals.

Currently, conventional medicine offers no known treatment that can effectively halt or reverse the fibrotic process in diseases such as pulmonary fibrosis and other similar conditions that may be caused by exposure to radiation or chemical pathogens, and permanent damage to lung tissue is often the result, if not in fact complete pulmonary failure. Now, however, adult stem cells may offer the first actual therapy which not only stops the progression of these various diseases but which also repairs and regenerates damaged lung tissue.

Adult stem cells derived from the placenta are already known to be highly potent and have been shown in a number of studies to engraft naturally into solid organs such as the lungs. In particular, the mesenchymal stem cells (MSCs) that are derived from placental blood and tissue are "immune privileged", "universal donor" cells, meaning that they do not pose any risk of immune rejection, even when administered allogeneically (when the donor and recipient are not the same person). In fact, these MSCs are known to possess a number of anti-inflammatory, immunomodulatory properties which are also of significant benefit to the recipient.

As Dr. Ornella Parolini, lead author of the study, explains, "The potential application of fetal membrane-derived (placental, i.e.) cells as a therapeutic tool for disorders characterized by inflammation and fibrosis is supported in previous studies. In line with the hypothesis that cells derived from the amniotic membrane have immunomodulatory properties and have been used as an anti-inflammatory agent, we set out to evaluate the effects of fetal membrane-derived (placental) cell transplantation in chemically-treated mice." Using intraperitoneal, intratracheal and intravenous delivery of the cells, the researchers then observed a consistent and significant anti-fibrotic effect in the laboratory mice, in whom the fibrosis had been artificially induced via the administration of bleomycin – a glycopeptide antibiotic that is commonly used in the chemotherapeutic treatment of some types of cancer, but from which pulmonary fibrosis is known to be a common side effect. Although the adult stem cells did not reduce the severity of the inflammation in this particular animal model, nevertheless there was a marked reduction in infiltration by neutrophil granulocytes (white blood cells) after the stem cell transplantation, whether autologous (in which the donor and recipient are the same person) or allogeneic (in which the donor and recipient are not the same person).

As Dr. Parolini further adds, "It is worth noting that the presence of neutrophils is associated with poor prognosis for several lung diseases. However, the mechanism by which placenta-derived cells might affect infiltration by neutrophils is not known. Our findings suggest that (placenta-derived) cells may prove useful for cell therapy of fibrotic diseases in the future."

As the authors conclude in their paper, "Our findings constitute further evidence in support of the hypothesis that placenta-derived cells could be useful for clinical application, and warrant further studies toward the use of these cells for the repair of tissue damage associated with inflammatory and fibrotic degeneration."

It has long been known that "Lewy bodies", one of the hallmarks of Parkinson’s disease and related types of neurodegenerative conditions, are formed from the aggregate accumulation of the synaptic protein alpha-synuclein. It has also been understood that the progression of such diseases is associated with the spreading of the Lewy bodies, which continue to infiltrate more and more regions of the brain. It has not previously been understood, however, exactly how the Lewy bodies are able to spread. Now, researchers are one step closer to a full elucidation of the underlying cellular and molecular mechanisms by which Lewy bodies ultimately invade the entire brain.

At the crux of the phenomenon is the neuron-to-neuron transmission of the alpha-synuclein itself – a new discovery made by collaborating scientists at the UC-San Diego School of Medicine and Konkuk University in Seoul, South Korea. According to Dr. Paula Desplats, lead author of the study and project scientist in the UC-San Diego Department of Neurosciences, "This discovery of cell-to-cell transmission of this protein may explain how alpha-synuclein aggregates can pass to new, healthy cells. We demonstrated how alpha-synuclein is taken up by neighboring cells, including grafted neuronal precursor cells, a mechanism that may cause Lewy bodies to spread to different brain structures."

The discovery is believed to have important implications for the use of stem cell therapies in the treatment of Parkinson’s disease and other "proteinopathies", since stem cells that are transplanted into the brains of patients are also vulnerable to eventual degeneration if a number of conditions are not suitable. As Dr. Eliezer Masliah, professor of neurosciences and pathology at the UC-San Diego School of Medicine, explains, "Our findings indicate that the stem cells used to replace lost or damaged cells in the brains of Parkinson’s disease patients are also susceptible to degeneration. Knowledge of the molecular basis of the intercellular transmission of alpha-synuclein may result in improved stem-cell-based therapies with long lasting benefits, by preventing the grafted cells to uptake alpha-synuclein or by making them more efficient in clearing the accumulated alpha-synuclein."

In most though not all Parkinson’s patients, the progression of alpha-synuclein is observable in a predictable pattern which begins in the lower brainstem and spreads first to the limbic system before ultimately attacking higher level cognitive functions in the neocortex. Prior to this study, previous findings had indicated that alpha-synuclein also spreads to transplanted neurons in Parkinson’s patients, an observation which led to a hypothesis of disease progression via neuron-to-neuron transmission. In the current study, which was specifically designed to test that hypothesis, the scientists discovered that the alpha-synuclein is transmitted between neurons via a process known as endocytosis, in which cells are able to absorb proteins from the extracellular media through their cell membranes. In addition to demonstrating that the accumulation of alpha-synuclein can be diminished by blocking the endocytic pathway, the scientists also found that inhibited lysosomal activity accelerates the accumulation of alpha-synuclein, since normal lysosomes would ordinarily help remove the accumulated aggregates. The scientists then demonstrated in a transgenic animal model how the alpha-synuclein is transmitted directly from host to grafted cells. Despite the fact that the laboratory animals had received fresh, healthy stem cells, within four weeks of the transplantation their brains had been overrun with Lewy bodies. Such findings would explain why human Parkinson’s patients who had received neuronal transplants usually succumb to the disease anyway, since the Lewy bodies that characterize Parkinson’s are still able to ravage the newly transplanted neurons.

As a result of these findings, researchers are now turning their attention to the strategic development of mechanisms by which stem cell therapy may be administered to Parkinson’s patients in conjunction with the blocking of endocytic pathways, and also in conjunction with the enhancement of normal lysosomal activity.

Today three universities in Nebraska have announced that they are to receive state grants in order to conduct stem cell research that strictly and exclusively involves adult stem cells, not embryonic stem cells. The recipients include Creighton University School of Medicine, the University of Nebraska Medical Center (UNMC), and the University of Nebraska at Lincoln, each of whom have been awarded a $150,000 research grant.

The three grants have been awarded in accordance with the Nebraska Stem Cell Research Act of 2008, which stipulates that neither state money nor state facilities may be used for research purposes in which the destruction of a human embryo is involved. Nonembryonic, adult stem cell research is strongly encouraged under the Act, and funding for the grants comes from the state’s tobacco lawsuit settlement funds.

The grants were recommended by Nebraska’s Stem Cell Advisory Committee, which consists of deans of the medical schools at Creighton and UNMC as well as four scientists from outside of Nebraska.

According to Tom Murray, dean of research at Creighton University School of Medicine, the grant is also in accordance with Creighton’s policy against the destruction of human embryos. Researchers at Creighton plan to use the grant money to conduct research on stem cells in mice for the development of therapeutic strategies in the treatment of hearing loss. Researchers at UNMC intend to use the grant money to study human adult stem cells in the treatment of vision loss.