precursor cells

Building a functional nervous system requires many types of neurons, each with their own role to play. This image provides a snapshot of neural precursor cells (pink and yellow) in a mouse embryo that will mature into different types of spinal cord neurons (blue), depending on the signals they receive. By studying the molecular instructions that guide these and other neurons to become one type of cell or another, scientists hope to better understand how the nervous system develops

Researchers discover novel function of protein linked to Alzheimer's disease

A research team led by the National Neuroscience Institute (NNI) has uncovered a novel function of the Amyloid Precursor Protein (APP), one of the main pathogenic culprits of Alzheimer’s disease. This discovery may help researchers understand how the protein goes awry in the brains of Alzheimer’s disease patients, and potentially paves the way for the development of innovative therapeutics to improve the brain function of dementia patients.

The findings were published in the prestigious scientific research journal Nature Communications last month. The study, which is led by Dr Zeng Li and her team from NNI, involved investigators from Duke-NUS Graduate Medical School and the Agency for Science and Technology (A*STAR).

Alzheimer’s disease is the most common form of dementia, which is set to rise significantly from the current 28,000 cases to 80,000 cases in 2030 among Singaporeans aged 60 and above. With a rapidly aging population, the burden of the disease will be profound affecting not just the person afflicted, but also the caregiver and family. While the exact cause of Alzheimer’s disease remains unknown, one of its pathological hallmarks is clear – the clumping of APP product in the brain when the protein is abnormally processed.

Finding out more about APP can help researchers gain a better understanding of the disease, and potentially identify biomarkers and therapeutic targets for it. However up till this point, little was known about the APP’s primary function in the brain.

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The seminferous tubule also contains Sertoli cells (green) embedded between the differentiating sperm cells (red). Sertoli cells nurture the developing sperm cells by secreting hormones and proteins required for spermatogenesis. Sertoli cells also establish and maintain the stem cell niche to ensure renewal of sperm cell precursors.

Image: A seminiferous tubule from a rat imaged at with a Phillips 501 scanning electron microscopy (1000X). The spermatozoa (red) are embedded in Sertoli cells (green). Spermatocytes (lavender) are also in the field. See previous slide for coloring protocol.

First new antibiotic in 30 years against superbug resistance.

A new antibiotic – the first in nearly 30 years – has been discovered by scientists who claim it appears to be as good, or even better, than many existing drugs with the potential to work against a broad range of fatal infections such as pneumonia and tuberculosis. Laboratory tests have shown the new antibiotic, called teixobactin, can kill some bacteria as quickly as established antibiotics and can cure laboratory mice suffering from bacterial infections with no toxic side-effects.

Studies have also revealed the prototype drug works against harmful bacteria in a unique way that is highly unlikely to lead to drug-resistance – one of the biggest stumbling blocks in developing new antibiotics. Test-tube studies, published in the journal Nature, showed that teixobactin was able to kill bacteria as quickly as the antibiotics vancomycin and oxacillin. Scientists at the University of Bonn in Germany have shown that teixobactin works in a unique way by binding to the fatty lipids that form the building blocks used by bacteria to manufacture their cell walls.

“This binding site represents a particular Achilles heel for antibiotic attack and this may also explain why resistance to teixobactin was not detected,” said Tanya Schneider of Bonn University. Professor Lewis said that the failure to detect any signs of resistance to teixobactin establishes a new paradigm in the development of antibiotics, which had assumed resistance will eventually occur. “Bacteria develop resistance by mutations in their proteins. The targets of teixobactin are not proteins, they are polymer precursors of cell wall building blocks so there is really nothing to mutate,” Professor Lewis said.

About 25,000 people a year in Europe alone already die from infections that are resistant to antibiotics and the World Health Organisation has described the rise of antibiotic-resistance as one of the most significant global risks facing modern medicine. Professor Mark Woolhouse, Professor of Infectious Disease Epidemiology at the University of Edinburgh, said: “Any report of a new antibiotic is auspicious, but what most excites me about [this research] is the tantalising prospect that this discovery is just the tip of the iceberg… It may be that we will find more, perhaps many more, antibiotics using these latest techniques. We should certainly be trying – the antibiotic pipeline has been drying up for many years now; we need to open it up again, and develop alternatives to antibiotics at the same time, if we are to avert a public health disaster.”

(To read more).

Light micrograph of a mouse embryo, approximately 10.5 days post-fertilisation by Jim Swoger. The specimen was stained with a fluorescent marker that highlights the presence of precursor cells to nerve tissue then chemically treated to make it optically transparent. (Royal Photographic Society’s exhibition)

Scientists Uncover Common Cell Signaling Pathway Awry in Some Types of Autism

Brain cells grow faster in children with some forms of autism due to distinct changes in core cell signaling patterns, according to research from the laboratory of Anthony Wynshaw-Boris, MD, PhD, chair of the department of genetics and genome sciences at Case Western Reserve University School of Medicine, and a member of the Case Comprehensive Cancer Center. Rapid cell growth can cause early brain overgrowth, a common feature in 20-30% of autistic children. But, the genetics of autistic children vary making it difficult to pinpoint common mechanisms underlying the disease.

“Autism is a complex disorder with multiple genetic and non-genetic factors,” explained Wynshaw-Boris. “Because the causes are diverse, it may help to define a subset of patients that have a common [symptom], in this case early brain overgrowth.”

In a study published in Molecular Psychiatry, Wynshaw-Boris and his colleagues started with skin cell samples from autistic children with enlarged brains and worked backward. Researchers in the laboratory “reprogrammed” donated skin cells to produce cells found in the developing brain including induced pluripotent stem cells and neural progenitor cells. Stem and progenitor cells are important therapeutic tools as they have the potential to grow into a multitude of cell types. The researchers hypothesized that even though the children in the study had different forms of autism, the precursor cells could be used to find common molecular and cellular mechanisms.

The researchers discovered that cells derived from autistic donors grew faster than those from control subjects and activated their genes in distinct patterns. Genes related to cell growth were unusually active, leading to more cells but fewer connections between them. This can cause faulty cell networks unable to properly transmit signals in the brain and enlarged heads during early development.

The researchers identified abnormal genes in the cells grown from autistic donors as belonging to the Wnt signaling pathway. The Wnt genes are critical for cell growth and serve as central players in cell networks, interfacing with multiple signaling pathways. Wynshaw-Boris previously identified the Wnt pathway as related to autism in mouse models of the disease. In a separate study published in Molecular Psychiatry earlier this year, the Wynshaw-Boris laboratory showed mice lacking Wnt genes display autism-like symptoms including social anxiety and repetitive behavior. The researchers could prevent these adult symptoms by treating the mice with medications that activate Wnt signaling in the uterus, during development.

“The Wnt pathway is one of the core developmental pathways conserved from invertebrates to humans. Our studies solidify previous suggestions that this pathway has a role in autism,” said Wynshaw-Boris.

Once they identified the dysfunctional signaling pathway in their reprogrammed autistic samples, the researchers (including the laboratories of Alysson Muotri, PhD at the University of California San Diego and Fred Gage, PhD at the Salk Institute) attempted to correct it by exposing mature nerve cells derived from autistic donors to drug compounds. One drug currently being tested in clinical trials for autism is insulin growth factor 1 (IGF-1). When the researchers added IGF-1 to nerve cells derived from autistic donors, neural networks were reestablished. It is unclear whether the positive effects of IGF-1 were on the Wnt pathway, and the exact compensatory mechanism requires further investigation.

Wynshaw-Boris’s studies in cell culture and mouse models of autism confirm improper Wnt signaling can lead to rapid brain cell growth and brain enlargement in the embryo, resulting in abnormal social behavior after birth. The next step will be to determine which genes are most impacted by Wnt signaling defects during early development, and how these changes result in abnormal behavior. “We would also like to find other drugs or compounds that may slow down the growth of the cells in tissue culture,” said Wynshaw-Boris. Together, these findings may help researchers unravel common ways brain cells can become impaired during early development in carefully chosen subsets of patients and contribute to symptoms across the autism spectrum.

Scientists find gene vital to central nervous system development

Scientists have identified a gene that helps regulate how well nerves of the central nervous system are insulated, researchers at Washington University School of Medicine in St. Louis report.

Healthy insulation is vital for the speedy propagation of nerve cell signals. The finding, in zebrafish and mice, may have implications for human diseases like multiple sclerosis, in which this insulation is lost.

The study appears Jan. 21 in Nature Communications.

Nerve cells send electrical signals along lengthy projections called axons. These signals travel much faster when the axon is wrapped in myelin, an insulating layer of fats and proteins. In the central nervous system, the cells responsible for insulating axons are called oligodendrocytes.

The research focused on a gene called Gpr56, which manufactures a protein of the same name. Previous work indicated that this gene likely was involved in central nervous system development, but its specific roles were unclear.

In the new study, the researchers found that when the protein Gpr56 is disabled, there are too few oligodendrocytes to provide insulation for all of the axons. Still, the axons looked normal. And in the relatively few axons that were insulated, the myelin also looked normal. But the researchers observed many axons that were simply bare, not wrapped in any myelin at all.

Without Gpr56, the cells responsible for applying the insulation failed to reproduce themselves sufficiently, according to the study’s senior author, Kelly R. Monk, PhD, assistant professor of developmental biology. These cells actually matured too early instead of continuing to replicate as they should have. Consequently, in adulthood, there were not enough mature cells, leaving many axons without insulation.

Monk and her team study zebrafish because they are excellent models of the vertebrate nervous system. Their embryos are transparent and mature outside the body, making them useful for observing developmental processes.

“We first saw this defect in the developing zebrafish embryo,” said first author Sarah D. Ackerman, a graduate student in Monk’s lab. “But it’s not simply a temporary defect that only results in delayed myelination. When I looked at fish that were six months old, I still saw this problem of undermyelinated axons.”

In a companion paper in the same issue of Nature Communications, senior author Xianhua Piao, MD, PhD, of Harvard University, and her co-authors, including Monk, showed similar defects in mice without Gpr56. In past work, Piao also has shown evidence that human defects in Gpr56 lead to brain malformations related to a lack of myelin.

“These are nice studies that arrived at the same conclusion independently,” said Monk, who is also with the Hope Center for Neurological Disorders at Washington University. “Our Harvard colleagues used mouse models while we used fish models. And Dr. Piao’s research in human patients suggests that similar mechanisms are at work in people.”

Monk also said that Gpr56 belongs to a large class of cell receptors that are common targets for many commercially available drugs, making the protein attractive for further research. The investigators pointed out its possible relevance in treating diseases associated with a lack of myelin, with particular interest in multiple sclerosis.

“In the case of MS, there are areas where the central nervous system has lost its myelin,” Monk said. “At least part of the problem is that the precursor myelin-producing cells are recruited to that area, but they fail to become adult cells capable of producing nerve cell insulation. Now, we have evidence that Gpr56 modulates the switch from precursor to adult cell.”

In theory, if the precursor cells can be pushed to mature into adulthood, they may become capable of producing myelin. According to Monk and Ackerman, possible future work includes using the zebrafish model system as a drug-screening tool to search for small molecules that may flip that switch.

Attractants prevent nerve cell migration

A vision is to implant nerve precursor cells in the diseased brains of patients with Parkinson’s and Huntington’s diseases, whereby these cells are to assume the function of the cells that have died off. However, the implanted nerve cells frequently do not migrate as hoped, rather they hardly move from the site. Scientists at the Institute for Reconstructive Neurobiology at Bonn University have now discovered an important cause of this: Attractants secreted by the precursor cells prevent the maturing nerve cells from migrating into the brain. The results are presented in the journal “Nature Neuroscience.”

One approach for treating patients with Parkinson’s or Huntington’s disease is to replace defective brain cells with fresh cells. To do this, immature precursor cells from neurons are implanted into the diseased brains; these cells are to then mature on-site and take over the function of the defective cells. “However, it has been shown again and again that the nerve cells generated by the transplant barely migrate into the brain but remain largely confined to the implant site,” says Prof. Dr. Oliver Brüstle, Director of the Institute for Reconstructive Neurobiology at Bonn University. Scientists have believed for a long time that this effect is associated with the fact that in the mature brain, there are unfavorable conditions for the uptake of additional nerve cells.

Immature and more mature nerve cells attract each other like magnets

The researchers from the Institute for Reconstructive Neurobiology of Bonn University have now discovered a fully unexpected mechanism to which the deficient migratory behavior of the graft-derived neurons can be attributed. The implanted cells mature at different rates and thus there is a mixture of the two stages. “Like magnets, the precursor cells which are still largely immature attract the nerve cells which have already matured further, which is why there is a sort of agglomeration,” says lead author Dr. Julia Ladewig, who was recently awarded a research prize of 1.25 million Euro by the North Rhine-Westphalian Stem Cell Network, which is supported by State Ministry of Science and Research.

The cause of the attractive force which has remained hidden to date involves chemical attractants which are secreted by the precursor cells. “In this way, the nerve precursor cells prevent the mature brain cells from penetrating further into the tissue,” says Dr. Philipp Koch, who performed the primary work for the study as an additional lead author, together with Dr. Ladewig.

The scientists had initially observed that, the more precursor cells contained in the transplant, the worse the migration of nerve cells is. In a second step, the researchers from the Institute for Reconstructive Neurobiology at Bonn University were able to decode and inactivate the attractants responsible for the agglomeration of mature and immature neurons. When the scientists deactivated the receptor tyrosine kinase ligands FGF2 and VEGF with inhibitors, mature nerve cells migrated better into the animal brains and dispersed over much larger areas.

Promising universal approach for transplants

“This is a promising new approach to solve an old problem in neurotransplantation,” Prof. Brüstle summarizes. Through the inhibition of attractants, the migration of implanted nerve precursor cells into the brain can be significantly improved. As the researchers have shown in various models with precursor cells from animals and humans, the mechanism is a fundamental principle which also functions across species. “However, more research is still needed to transfer the principle into clinical application,” says Prof. Brüstle.