neuroregeneration

Stem cell-based bioartificial tissues and organs

Surgeon Paolo Macchiarini has made his name by successfully transplanting bioengineered stem cell-based trachea, composed of both artificial and biological material. He now plans to use the technique to recreate more complex tissues, such as the oesophagus and diaphragm or organs such as the heart and lungs. He has also made an experimental attempt to regenerate brain in mice and rats. This is part of the news he will be presenting during his seminar at the scientific AAAS Annual Meeting in Boston.

In June 2011, media all over the world reported about a ground breaking transplant, where a patient received an artificial trachea covered in his own stem cells. The result was an artificial windpipe with biological functions. To date, five operations have been carried out using this technique.

“We learn something from each operation. This means we can develop and refine the technique. We are also evaluating how we can transfer our experiences to other fields, such as neurology. The aim is to make as much use of the body’s own healing potential as we can”, says Paolo Macchiarini, Professor of Regenerative Surgery at Karolinska Institutet, and responsible for the surgery.

At the AAAS Annual Meeting, he will talk about how he believes the technology can be used in the future. This will include:

  • The plan to operate on a 2 year-old girl in the USA in March. The girl was born without a trachea and has lived her entire life in intensive care, where she breathes through a tube placed in the oesophagus and connected directly to the lungs. Without a new trachea, she will never be able to leave the hospital. This will be the first time the procedure is conducted on a small child. It is also the first time the procedure will be conducted on an individual without a trachea - as previously, diseased organs have been replaced.
  • There are also plans to transplant the oesophagus, an organ that is more complex than a trachea as it has muscles.
  • In experimental trials on rats, the research team has investigated the possibility to replace brain matter that has been damaged by serious trauma sustained from events such as traffic accidents, gunshot wounds or surgery. The aim is to replace the lost brain matter with a cultivated stem cell based substance and in turn, avoid neurological damage. The experimental attempt that has been conducted on rats and mice has shown positive results.
  • On two occasions, severely injured patients with acute refractory lung failure received stem cell based therapy showing immediate functional improvement. Although both patients died as a consequence of multi-organ failure, the result has provided the first evidence that stem cell therapy can be a promising alternative to restore function in certain damaged organs - without the need for them to be removed and replaced with healthy donor organs.

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Neuroregeneration

Neuroregeneration refers to the regrowth or repair of nervous tissues, cells or cell products. Such mechanisms may include generation of new neurons, glia, axons, myelin, or synapses. Neuroregeneration differs between the peripheral nervous system (PNS) and the central nervous system (CNS) by the functional mechanisms and especially the extent and speed. When an axon is damaged, the distal segment undergoes Wallerian degeneration, losing its myelin sheath. The proximal segment can either die by apoptosis or undergo the chromatolytic reaction, which is an attempt at repair. In the CNS, synaptic stripping occurs as glia foot processes invade the dead synapse.

Nervous system injuries affect over 90,000 people every year. It is estimated that spinal cord injuries alone affect 10,000 each year. As a result of this high incidence of neurological injuries, nerve regeneration and repair, a subfield of neural tissue engineering, is becoming a rapidly growing field dedicated to the discovery of new ways to recover nerve functionality after injury. The nervous system is divided into two parts: the central nervous system, which consists of the brain and spinal cord, and the peripheral nervous system, which consists of cranial and spinal nerves along with their associated ganglia. While the peripheral nervous system has an intrinsic ability for repair and regeneration, the central nervous system is, for the most part, incapable of self-repair and regeneration. There is currently no treatment for recovering human nerve function after injury to the central nervous system. In addition, multiple attempts at nerve re-growth across the PNS-CNS transition have not been successful. There is simply not enough knowledge about regeneration in the central nervous system. In addition, although the peripheral nervous system has the capability for regeneration, much research still needs to be done to optimize the environment for maximum regrowth potential. Nerve regeneration is important clinically, as it is part of the pathogenesis of many diseases, including multiple sclerosis.

Growth Factor Regenerates Damaged Nerves Without Sprouting New Blood Vessels

Read the full article Growth Factor Regenerates Damaged Nerves Without Sprouting New Blood Vessels at NeuroscienceNews.com.

Researchers at the University of Illinois at Chicago College of Medicine have found that a growth factor can regenerate damaged peripheral nerves without causing the growth of new blood vessels — making it a unique candidate to treat nerve damage in areas of the body where the proliferation of blood vessels would be a drawback.

The research is in PNAS. (full open access)

Research: “VEGF-B selectively regenerates injured peripheral neurons and restores sensory and trophic functions” by Victor H. Guaiquil, Zan Pan, Natalia Karagianni, Shima Fukuoka, Gemstonn Alegre, and Mark I. Rosenblatt in PNAS. doi:10.1073/pnas.1407227111 (http://www.pnas.org/content/early/2014/11/12/1407227111.full.pdf+html)

Image: Neural regeneration was improved when VEGF-B was delivered to the cornea. This image is for illustrative purposes only. Credit PublicDomainPictures.

Scientists identify clue to regrowing nerve cells

Researchers at Washington University School of Medicine in St. Louis have identified a chain reaction that triggers the regrowth of some damaged nerve cell branches, a discovery that one day may help improve treatments for nerve injuries that can cause loss of sensation or paralysis.

The scientists also showed that nerve cells in the brain and spinal cord are missing a link in this chain reaction. The link, a protein called HDAC5, may help explain why these cells are unlikely to regrow lost branches on their own. The new research suggests that activating HDAC5 in the central nervous system may turn on regeneration of nerve cell branches in this region, where injuries often cause lasting paralysis.

“We knew several genes that contribute to the regrowth of these nerve cell branches, which are called axons, but until now we didn’t know what activated the expression of these genes and, hence, the repair process,” said senior author Valeria Cavalli, PhD, assistant professor of neurobiology. “This puts us a step closer to one day being able to develop treatments that enhance axon regrowth.”

The research appears Nov. 7 in the journal Cell.

Axons are the branches of nerve cells that send messages. They typically are much longer and more vulnerable to injury than dendrites, the branches that receive messages.

In the peripheral nervous system — the network of nerve cells outside the brain and spinal column — cells sometimes naturally regenerate damaged axons. But in the central nervous system, comprised of the brain and spinal cord, injured nerve cells typically do not replace lost axons.

Working with peripheral nervous system cells grown in the laboratory, Yongcheol Cho, PhD, a postdoctoral research associate in Cavalli’s laboratory, severed the cells’ axons. He and his colleagues learned that this causes a surge of calcium to travel backward along the axon to the body of the cell. The surge is the first step in a series of reactions that activate axon repair mechanisms.

In peripheral nerve cells, one of the most important steps in this chain reaction is the release of a protein, HDAC5, from the cell nucleus, the central compartment where DNA is kept. The researchers learned that after leaving the nucleus, HDAC5 turns on a number of genes involved in the regrowth process. HDAC5 also travels to the site of the injury to assist in the creation of microtubules, rigid tubes that act as support structures for the cell and help establish the structure of the replacement axon.

When the researchers genetically modified the HDAC5 gene to keep its protein trapped in the nuclei of peripheral nerve cells, axons did not regenerate in cell cultures. The scientists also showed they could encourage axon regrowth in cell cultures and in animals by dosing the cells with drugs that made it easier for HDAC5 to leave the nucleus.

When the scientists looked for the same chain reaction in central nervous system cells, they found that HDAC5 never left the nuclei of the cells and did not travel to the site of the injury. They believe that failure to get this essential player out of the nucleus may be one of the most important reasons why central nervous system cells do not regenerate axons.

“This gives us the hope that if we can find ways to manipulate this system in brain and spinal cord neurons, we can help the cells of the central nervous system regrow lost branches,” Cavalli said. “We’re working on that now.”

Mycotoxins Present Food Deteriorates Neuroregeneration

Researchers showed the potential negative effect on neuroregeneration caused by Ochratoxine A, a mycotoxin found in many types of food. The research, carried out in the Faculty of Health Sciences of CEU Cardenal Herrera University, in cooperation with the University of Valencia, was published …

Read more Mycotoxins Present Food Deteriorates Neuroregeneration

Scientists Coax Brain to Regenerate Cells Lost in Huntington’s Disease

Researchers have been able to mobilize the brain’s native stem cells to replenish a type of neuron lost in Huntington’s disease. In the study, which appears today in the journal Cell Stem Cell, the scientists were able to both trigger the production of new neurons in mice with the disease and show that the new cells successfully integrated into the brain’s existing neural networks, dramatically extending the survival of the treated mice.

“This study demonstrates the feasibility of a completely new concept to treat Huntington’s disease, by recruiting the brain’s endogenous neural stem cells to regenerate cells lost to the disease,” said University of Rochester Medical Center (URMC) neurologist Steve Goldman, M.D., Ph.D., co-director of Rochester’s Center for Translational Neuromedicine.

Huntington’s disease is an inherited neurodegenerative disease characterized by the loss of a specific cell type called the medium spiny neuron, a cell that is critical to motor control. The disease, which affects some 30,000 people in the U.S., results in involuntary movements, problems with coordination, and, ultimately, in cognitive decline and depression. There is currently no way to slow or modify this fatal disease.

For Goldman, the idea behind his strategy to treat the disease emerged from his decades-long study of neural plasticity in canaries. Songbirds like canaries have intrigued biologists because of their ability – unique in the animal kingdom – to lay down new neurons in the adult brain. This process, called adult neurogenesis, was first discovered by Goldman and Fernando Nottebohm of the Rockefeller University in the early 1980s, when the two realized that when learning new songs new neurons were added to regions of the bird’s brain responsible for vocal control.

“Our work with canaries essentially provided us with the information we needed to understand how to add new neurons to adult brain tissue,” said Goldman. “Once we mastered how this happened in birds, we set about how to replicate the process in the adult mammalian brain.”

Humans already possess the ability to create new neurons. Goldman’s lab demonstrated in the 1990s that a font of neuronal precursor cells exist in the lining of the ventricles, structures found in the core of the human brain. In early development, these cells are actively producing neurons. However, shortly after birth the neural stem cells stop generating neurons and instead produce glia, a family of support cells that pervade the central nervous system. Some parts of the human brain continue to produce neurons into adulthood, the most prominent example is the hippocampus where memories are formed and stored. But in the striatum, the region of the brain that is devastated by Huntington’s disease, this capability is “switched off” in adulthood.

Goldman and his team spent the past decade attempting to unravel the precise chemical signaling responsible for instructing neural stem cells when to create neurons and when to create glia cells. One of the most critical clues came directly from the earlier research with canaries. In the part of the bird’s brain were new songs are acquired and neurons added, the scientists observed the regulated expression of a protein called brain derived neurotrophic factor, or BDNF.  When the production of this protein is triggered, the local neural stem cells are instructed to produce neurons.

At the same time, the scientists also realized that they had to simultaneously suppress the bias of these stem cells to produce glia. They found that when BDNF was combined with another molecule called noggin – a protein that inhibits the chemical pathway that dictates the creation of glial cells – they could successfully switch the stem cell’s molecular machinery over to the production of neurons.

The next challenge was how to deliver these two proteins – BDNF and noggin – precisely and in a sustained fashion to the area of the brain involved in Huntington’s disease. To do so, they partnered with scientists at the University of Iowa to modify a viral gene therapeutic, called an adeno-associated virus, to deliver the necessary molecular instructions to the neural stem cells.

The virus infected the target cells in the brains of mice with Huntington’s disease and triggered the sustained over-expression of both BDNF and noggin. This, in turn, activated the neighboring neural stem cells which began to produce medium spiny motor neurons. The new neurons were continuously generated and migrated to the striatum, the region of the brain impacted by Huntington’s disease, where they then integrated into the existing neuronal networks. 

The researchers were able to significantly extend the survival of the treated mice, in some cases doubling their life expectancy. The researchers also devised a way to tag the new neurons and observed that the cells extended fibers to distant targets within the brain and establish electrical communication. 

After having established the ability to generate new replacement neurons in mouse models of Huntington’s disease, the researchers also demonstrated that they could replicate this technique in the brains of normal squirrel monkeys, a step that brings the research much closer to tests in humans. 

“The sustained delivery of BDNF and noggin into the adult brain was clearly associated with both increased neurogenesis and delayed disease progression,” said Goldman. “We believe that our data suggest the feasibility of this process as a viable therapeutic strategy for Huntington’s disease.”

New biomaterials promote neuroregeneration after a brain injury

Professor José Miguel Soria, a member of the Institute of Biomedical Sciences, Universidad CEU Cardenal Herrera, has co-directed with Professor Manuel Monleón of the Universitat Politècnica de València a study on the compatibility of polymeric biomaterials in the brain and its effectiveness to favour neuroregeneration in areas with some kind of damage or brain injury.  

The research carried out has shown that these types of implants, made of a biocompatible synthetic material, are colonized within two months by neural progenitor cells and irrigated by new blood vessels. This allows the generation, within these structures, of new neurons and glia, capable of repairing injured brain tissue caused by trauma, stroke or neurodegenerative disease, among other causes.

The synthetic structures used in this study are made with a porous and biocompatible polymeric material called acrylate copolymer. In the first phase of the project, the structures have been studied in vitro by implanting them into neural tissue, and subsequently also in vivo, when implanted in two areas of the adult rat brain: the cerebral cortex and the subventricular zone, the most important source of generation of adult neural stem cells.

The study has confirmed the high biocompatibility of polymeric materials, such as acrylate copolymer, with brain tissue and opens new possibilities of the effectiveness of the implementation of these structures in the brain, seeking optimum location for developing regenerative strategies of the central nervous system.

Furthermore, the results are particularly relevant when one considers that in the adult brain neuroregeneration capacity is more limited than in younger individuals and that the main impediment for this is the lack of revascularization of damaged tissue, something that the biomaterial studied has shown to favour.

Worm research: Right combination of sugars regulates brain development

If the development of our nervous system is disturbed, we risk developing serious neurological diseases, impairing our sensory systems, movement control or cognitive functions. This is true for all organisms with a well-developed nervous system, from man to worm. New research from BRIC, University of Copenhagen reveals how a tiny molecule called mir-79 regulates neural development in roundworms. The molecule is required for correct migration of specific nerve cells during development and malfunction causes defects in the nervous system of the worm. The research has just been published in the journal Science.

Hundreds of worms lie in a small plastic plate under the laboratory microscope. Over the last three years, the group of Associate Professor Roger Pocock has used the roundworm C. elegans tostudy the development of the nervous system. They have just made an important discovery.

“Our new results show that a small molecule called mir-79 is indispensable for development of the worm’s nervous system. mir-79 acts by equipping special signal molecules with a transmitter, which tells the nerve cells how they should migrate during development of the worm. If we remove mir-79 with gene technology, development of the worm nervous system goes awry", says postdoc Mikael Egebjerg Pedersen, who is responsible for the experimental studies.

mir-79 adds just the right combination of sugar

The research shows that mir-79 acts by controlling the addition of certain groups of sugars to selected signaling molecules. In the world of cells, sugar molecules act as transmitters.

When the nerve cells come into contact with the sugar-transmitters, they are informed where to locate themselves during neural development. If the researchers remove mir-79, the migration of the nerve cells is misguided causing neuronal defects in the worms.

“It has earlier been shown that signaling molecules guide nerve migration, but our research shows that mir-79 regulates nerve cell migration by controlling the correct balance of sugar-transmitters on signaling molecules. If mir-79 does not function, the worm nervous system is malformed. In the wild, such defects would be harmful for worm survival", explains Roger Pocock who leads the research group behind the finding.

Worm studies reveal important clues for neuronal repair

A version of mir-79 called mir-9 is found in humans. Therefore, these results are important for understanding how our nervous system develops during fetal development. In addition, the results add to the understanding of how nerve cells may be stimulated to repair damage in our brain or spinal cord.

“Our nervous system is a tissue which is not easily repaired after damage. So, how certain molecular cues can stimulate nerve cells to migrate is an important brick in the puzzle. This will enable us to understand how nerve tissue can be regenerated after, for example, a stroke or an accident. If we can use such knowledge to mimic the signals, we may be able to stimulate nerve cells to migrate into a damaged area", says Roger Pocock.

Worms are a fantastic model to study how the nervous system develops and how nerve cells form neuronal circuits. Most of the genes that control nervous system development in the worm are also found in humans. At the same time, the reduced complexity of the worm nervous system allows researchers to investigate central biological mechanisms. With new technologies they can mark single cells or molecules, and as worms are transparent, the researchers can track the marked molecules or cells live during worm development.

The next step for the researchers is to investigate how the regulatory pathway they have revealed is regulated in cultures of human cells.