Neuroregeneration – Center for Regenerative Biotherapeutics – Mayo …

Spinal neuron growth cones

Fluorescent spinal neurons in the developing Xenopus embryo

Hippocampal neuron immunostained to reveal green microtubule cytoskeleton

Nerve muscle co-culture

Contact adhesions in the nerve growth cone (paxillin in red, microtubules in green)

Substrate adhesions in the growth cone induced by brain derived neurotrophic factor

The complex, delicate structures that make up the nervous system the brain, spinal cord and peripheral nerves are susceptible to various types of injury ranging from trauma to neurodegenerative diseases that cause progressive deterioration: Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease), multiple sclerosis and multiple system atrophy.

Unfortunately, because of the complexity of the brain and spinal cord, little spontaneous regeneration, repair or healing occurs. Therefore, brain damage, paralysis from spinal cord injury and peripheral nerve damage are often permanent and incapacitating.

Patients with serious nervous system injuries or strokes often require lifelong assistance, which puts a tremendous burden on patients, their families and society. Innovative, paradigm-shifting strategies are required to advance treatment of neurological injury. The neuroregeneration research at Mayo Clinic is at the forefront of healing the nervous system.

For an in-depth look at neuroregeneration, see the neuroregenerative medicine at Mayo Clinic booklet.

Mayo Clinic clinicians, scientists, engineers and other specialists in the Center for Regenerative Biotherapeutics are taking a multidisciplinary integrative approach to neuroregeneration for a number of devastating neurological conditions. The research is multifaceted, ranging from basic science discovery to clinical applications.

Alzheimer's disease. Alzheimer's disease is the major cause of dementia in older adults, with progressive loss of neurons in areas of the brain responsible for learning and memory. Efforts in Alzheimer's disease research focus on understanding why neurons degenerate in brains with Alzheimer's disease and how to either slow down the process or replace lost neurons.

Mayo researchers are investigating the effects of restoring cerebrovascular function, through transplantation of induced pluripotent stem (iPS) cell-derived vascular progenitor cells, on amyloid pathology and cognitive function in amyloid Alzheimer's disease model mice. The iPS cells converted from skin fibroblasts by transducing four transcription factors (Oct3/4, SOX2, Klf4, c-Myc) have the potential to generate all tissues in the body, including vascular cells.

This innovative approach will likely allow for rational designs of vascular regenerative therapy against Alzheimer's disease.

Anthony J. Windebank, M.D., and Nathan P. Staff, M.D., Ph.D., both neurologists and researchers at Mayo Clinic, discuss the latest research into ALS treatments.

Multiple sclerosis. While scientists understand much about the damage that happens to nerves and their insulating sheath (myelin) during multiple sclerosis (MS)and how the immune system causes this damage, the exact reasons for the immune system attack are very poorly understood. The lack of understanding of the exact cause of MS is a challenge for the development of effective therapies, and Mayo Clinic laboratories are working to better understand this disease.

Protecting nerves and myelin from damage, or repairing myelin after it's been damaged, also holds potential for the treatment of MS. Injury to nerves and myelin can be severe in MS and is the major cause of functional impairments. However, spontaneous repair of this damage is sometimes observed in people with MS. Researchers in the Center for Regenerative Biotherapeutics are actively engaged in developing therapies designed to stimulate this repair and thereby promote recovery of lost function.

Antibodies that bind to myelin and nerve cells and protect nerves from damage and stimulate myelin regeneration have been identified. A recent study also has found that regeneration of the myelin sheath can be stimulated by small, folded DNA molecules (aptamers).

Multiple system atrophy.Multiple system atrophy (MSA) is a progressive, fatal neurodegenerative disorder. The hallmark of the disease is glial cytoplasmic inclusions. The main component of glial cytoplasmic inclusions is alpha-synuclein. Aggregation of alpha-synuclein microfibrils leads to a chain of events, including microglial activation, inflammation, and glial and neuronal degeneration. The likely mechanisms involved include growth factor (BDNF, GDNF) deficiency, toxic cytokines and oxidative injury.

Research focuses on the prevention of alpha-synuclein aggregation by drugs such as rifampicin or paroxetine; the use of mesenchymal stem cells to provide and deliver growth factors; and attacking microglial activation and the inflammatory response by agents such as intravenous immunoglobulin.

Immune response and neuroregeneration. Researchers in the Mayo Clinic Center for Regenerative Biotherapeutics are developing numerous approaches to attenuate specific immune cell types in central nervous system (CNS) inflammation and applying strategies to a variety of diseases, including inflammation developing in the course of stem cell transplant, gene therapy or factor-driven regeneration of CNS tissues.

Studies have demonstrated a therapeutic effect in reducing motor dysfunction and blood-brain barrier disruption in model systems of multiple sclerosis through the removal of antigen-specific CD8 T cell responses. By optimizing the imaging of neuroinflammation with high-resolution confocal microscopy, small animal MRI and the profiling of CNS-infiltrating immune cells using flow cytometry, it's possible to isolate and phenotype CNS-infiltrating immune cells in vivo and visualize in real time the events leading to inflammatory destruction of nervous tissue.

Spinal cord repair. Regrowth of nerve fibers (axons) is essential to repair and functional recovery of the spinal cord. Tissue destruction with cysts and gliosis at the site of injury forms a barrier to regeneration.

Ongoing research is using tissue engineering with biodegradable polymer scaffolds (PLGA, PCLF, OPF) loaded with different growth-promoting cells (Schwann cells, neural progenitor cells, mesenchymal stem cells) and different growth factors (GDNF, NT3, BDNF) to bridge the gap, and to promote axonal regeneration and functional restoration in the spinal cords of rats and mice, eventually for future use in patients.

Further, Mayo Clinic researchers are investigating the effects of exercise training and local delivery of steroids on axon regeneration and functional recovery.

Peripheral nerve regeneration and repair. The Center for Regenerative Biotherapeutics is developing strategies to expand the time window of opportunity and improve the functional recovery followingperipheral nerve injury and repair.

One strategy is to apply polymer microspheres to deliver vascular endothelial growth factor (VEGF) to the nerve repair site in a controlled sustainable release manner. VEGF promotes angiogenesis and neurogenesis, and thus leads to a better functional outcome and larger window of opportunity for the nerve to be permissive to prolonged regeneration.

The other strategy is to counteract the lack of healthy Schwann cells at the nerve repair site by supplementing functioning Schwann cells derived from nerves prepared in an in vitro system or Schwann cells induced from stem cells of the adipose tissue.

Novel animal models are being developed to delineate the nature and time course of denervation muscle changes; identify the key indicators of muscle receptivity, including electromyographic changes, muscle fiber type changes and changes of myogenic genes; and evaluate the impact of these changes on nerve regeneration and the potential success of a nerve repair.

Stroke neuroregeneration. After stroke, neurons near the penumbra are vulnerable to delayed but progressive damage as a result of ischemia. There is no effective treatment to rescue such dying neurons. Researchers in the Center for Regenerative Biotherapeutics hypothesized that mesenchymal stem cells (MSC) can rescue damaged neurons after exposure to oxygen-glucose deprivation (OGD) stress.

Studies have demonstrated that the MSC can differentiate into bone, cartilage and fat tissues. Experiments in animal models of hemorrhagic stroke showed MSC therapy improves limb function. Taken together, this data will form the basis for using MSC to treat patients with recent hemorrhagic stroke.

Neuro-oncology and neuroregenerative research. Research currently focuses on invasive brain tumors (gliomas) for which patients receive a very poor prognosis. However, there are other brain tumors oligodendroglioma and astrocytoma that have a much better prognosis. Mayo Clinic researchers are interested in the mutations that are involved in the development of each of these different tumor types and why the tumors behave differently.

A target locus in a gene-poor region initially discovered by genome scanning has been identified. Research efforts are focused on studying the function of this alteration. Using mouse models, murine and human neural stem cells, and human induced pluripotent stem cells, Mayo researchers are investigating how the alteration modifies glial cell development.

Neuroregeneration and inflammation. The limited capacity for repair in the nervous system is a significant medical challenge. The Center for Regenerative Biotherapeutics is developing new tools to effectively control the process of neural injury and degeneration and to create a microenvironment that enhances the capacity for innate repair and the efficacy of other regeneration strategies, including neural cell replacement and neurorehabilitation.

Research efforts focus on how highly druggable proteases (kallikreins) can be targeted to prevent the complex cascade of tissue injury and aberrant reorganization that is a well-recognized component of CNS trauma and which is increasingly recognized as an integral factor underlying the progression of many neurological disorders, including those classified as neurodegenerative or neuroinflammatory as well as those having an oncogenic basis.

Efforts are directed at understanding the physiological and pathophysiological consequences of a family of G protein-coupled receptors (protease-activated receptors, or PARs), and determining whether PARs or the proteases that activate them can be targeted therapeutically to prevent pathogenesis and to promote CNS plasticity and repair to improve patient functional outcomes.

Deep brain stimulation for Alzheimer's disease. Anecdotal and initial trial reports concerning deep brain stimulation (DBS) to the fornix and hypothalamus have been associated with improvement in memory function and reductions in expected cognitive decline in patients with early Alzheimer's disease. The fornix constitutes the major inflow and output pathway from the hippocampus and medial temporal lobe.

Mayo researchers have started an innovative pilot study of dual-hemispheric stimulation of the subthalamic nucleus and fornix and hypothalamus to determine if this approach may have positive effects in attenuating cognitive decline. If this study provides positive data, then the potential of using DBS of the fornix as a treatment for Alzheimer's disease will be considered.

Pediatric anesthesia, apoptosis and safety. Exposure to multiple anesthetics at a young age may be associated with later problems, such as learning disabilities and attention-deficit/hyperactivity disorder. Researchers in the Center for Regenerative Biotherapeutics are working on a large project involving the detailed testing of 1,000 children to try to better define what injury (if any) may be associated with anesthetic exposure. This information will be important to see if this is really a problem in clinical practice, and if so, to change practice to minimize problems.

Researchers are performing detailed neurodevelopmental testing on a sample from a birth cohort of children, including a testing battery previously used in primates shown to be affected by anesthesia exposure. The aim is to confirm (or refute) prior findings and provide for the first time a detailed phenotype of anesthesia-associated injury (if present).

Neurogenesis. By increasing the understanding of the molecular targets involved in regulation of adult hippocampal neurogenesis (neuron generation) and related behavioral responses altered in neuropathological conditions, scientists can study underlying cellular and molecular mechanisms that regulate the production, maturation and integration of new neurons in the circuitry, and how aberrant neurogenesis plays a role in disease pathogenesis. Researchers are employing behavioral neuroscience to quantify cognition such as learning, memory and anxiety.

Recognizing the therapeutic potential of adult neurogenesis, Mayo Clinic researchers are characterizing treatment systems and clinically approved medication that can allow dictation of neuronal development in the correct direction. The long-term goal is to harness the regenerative capacity of adult neurogenesis toward an optimal clinical outcome and improved treatment options for brain disorders.

Neurorehabilitation. This research focuses on improving participation and the quality of life in people whose brain functions have been altered by injury or disease. The focus is regenerative in that improved behavioral performance is possible only when adaptive anatomic and physiological change occurs within and between brain systems in response to therapeutic intervention.

By developing treatment approaches that lead to improved function and independence, researchers in the Center for Regenerative Biotherapeutics promote the adaptive regenerative changes in brain function that make this improved behavioral performance possible.

Transduction mechanisms mediating bidirectional nerve growth. Cues released from the breakdown of myelin after injury in the brain and spinal cord may act as chemorepellents and inhibit axon extension, which limits functional recovery. In contrast, positive cues such as neurotrophins can promote axon extension and elicit chemoattraction.

This research aims to determine how chemotropic cues in the microenvironment guide nerve growth and how dysfunctional guidance mechanisms can cause disease. Understanding these mechanisms and discovering methods to manipulate them are important for developing new therapies to promote neural regeneration after degenerative disease or injury.

Researchers are determining how chemotropic cues in the microenvironment guide nerve growth and how dysfunctional guidance mechanisms can cause disease. This will allow scientists to define the spatiotemporal signal transduction mechanisms by which nerve growth cones detect extracellular guidance cues and dynamically regulate cellular effectors to control the direction of axon extension during normal embryonic development and neural regeneration after injury.

Longer term, the research goal is to define mechanisms for priming and guiding regenerating axons to appropriate synaptic targets to complete functional circuits.

Neuroregenerative Medicine at Mayo Clinic (PDF)

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