Neuroregeneration

  • Spinal neuron growth cones

    Spinal neuron growth cones

  • Fluorescent spinal neurons in the developing Xenopus embryo

    Fluorescent spinal neurons in the developing Xenopus embryo

  • Hippocampal neuron immunostained to reveal green microtubule cytoskeleton

    Hippocampal neuron immunostained to reveal green microtubule cytoskeleton

  • Nerve muscle co-culture

    Nerve musculus co-culture

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

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

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

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

The complex, delicate structures that make upward the nervous system — the encephalon, spinal cord and peripheral nerves — are susceptible to various types of injury ranging from trauma to neurodegenerative diseases that cause progressive deterioration: Alzheimer'south disease, Parkinson'due south disease, amyotrophic lateral sclerosis (ALS, too known as Lou Gehrig's disease), multiple sclerosis and multiple arrangement 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 string injury and peripheral nerve harm are often permanent and incapacitating.

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

For an in-depth wait at neuroregeneration, run across the neuroregenerative medicine at Mayo Clinic booklet.

Focus areas

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

Disease-specific research

  • Alzheimer's illness. Alzheimer's disease is the major crusade 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 enquiry focus on agreement why neurons degenerate in brains with Alzheimer'south disease and how to either slow downward the procedure or replace lost neurons.

    Mayo researchers are investigating the furnishings of restoring cerebrovascular office, through transplantation of induced pluripotent stalk (iPS) prison 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 past transducing iv transcription factors (Oct3/4, SOX2, Klf4, c-Myc) take 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.

  • Amyotrophic lateral sclerosis. Mayo Clinic researchers are testing a cell-based therapy for amyotrophic lateral sclerosis (ALS). Still in its early stages, this research uses adipose-derived mesenchymal stem cells from the patient'due south own body. These cells are modified in the laboratory and delivered back into the patient'south nervous system to promote neuron regeneration.

Anthony J. Windebank, M.D., and Nathan P. Staff, Grand.D., Ph.D., both neurologists and researchers at Mayo Dispensary, 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 allowed system causes this damage, the exact reasons for the immune system attack are very poorly understood. The lack of understanding of the verbal cause of MS is a claiming for the development of effective therapies, and Mayo Clinic laboratories are working to ameliorate understand this disease.

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

    Antibodies that bind to myelin and nervus cells and protect fretfulness from damage and stimulate myelin regeneration have been identified. A recent study also has found that regeneration of the myelin sheath can exist stimulated by pocket-size, folded DNA molecules (aptamers).

  • Parkinson's disease. Researchers are studying the genetic contribution to susceptibility to Parkinson's disease through the establishment of a bank of skin and iPS cell lines from people with Parkinson's disease. Having a cell line like this provides the ability to generate the cells that dice in neurodegenerative disease, assuasive researchers to better empathize the genetic cause of this status and develop new treatments for these disorders in the future.

  • Multiple arrangement atrophy. Multiple system atrophy (MSA) is a progressive, fatal neurodegenerative disorder. The hallmark of the disease is glial cytoplasmic inclusions. The principal component of glial cytoplasmic inclusions is blastoff-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 assemblage by drugs such as rifampicin or paroxetine; the use of mesenchymal stalk cells to provide and deliver growth factors; and attacking microglial activation and the inflammatory response by agents such as intravenous immunoglobulin.

Clinical treatments

  • Allowed response and neuroregeneration. Researchers in the Mayo Clinic Center for Regenerative Medicine are developing numerous approaches to attenuate specific immune prison cell types in central nervous organization (CNS) inflammation and applying strategies to a multifariousness of diseases, including inflammation developing in the course of stalk cell transplant, gene therapy or gene-driven regeneration of CNS tissues.

    Studies have demonstrated a therapeutic consequence 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. Past optimizing the imaging of neuroinflammation with loftier-resolution confocal microscopy, small brute 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 fourth dimension 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 string. Tissue destruction with cysts and gliosis at the site of injury forms a barrier to regeneration.

    Ongoing research is using tissue technology with biodegradable polymer scaffolds (PLGA, PCLF, OPF) loaded with dissimilar growth-promoting cells (Schwann cells, neural progenitor cells, mesenchymal stalk cells) and unlike 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 preparation and local delivery of steroids on axon regeneration and functional recovery.

  • Peripheral nerve regeneration and repair. The Heart for Regenerative Medicine is developing strategies to expand the time window of opportunity and improve the functional recovery following peripheral nerve injury and repair.

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

    The other strategy is to annul the lack of healthy Schwann cells at the nervus repair site by supplementing performance Schwann cells derived from nerves prepared in an in vitro system or Schwann cells induced from stalk cells of the adipose tissue.

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

  • Nerve prison cell regrowth: Axogenesis. Mayo researchers are using zebrafish every bit an fauna model system to investigate how special cues in the brain and spinal cord can entice or block nerve cell growth — experiments that assistance scientists understand why conditions at the site of nerve injury retard regeneration. This work is providing new agreement into how nervus cells abound during development of the nervous system and how nerve regeneration might be improved afterwards injury.

  • Stroke neuroregeneration. Later stroke, neurons near the penumbra are vulnerable to delayed but progressive harm every bit a result of ischemia. There is no constructive treatment to rescue such dying neurons. Researchers in the Center for Regenerative Medicine hypothesized that mesenchymal stem cells (MSC) tin rescue damaged neurons subsequently 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. Enquiry currently focuses on invasive encephalon tumors (gliomas) for which patients receive a very poor prognosis. Still, at that place are other encephalon tumors — oligodendroglioma and astrocytoma — that have a much improve prognosis. Mayo Dispensary researchers are interested in the mutations that are involved in the development of each of these different tumor types and why the tumors comport 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 man neural stalk cells, and man induced pluripotent stem cells, Mayo researchers are investigating how the alteration modifies glial cell development.

  • Neuroregeneration and inflammation. The express capacity for repair in the nervous arrangement is a significant medical claiming. The Centre for Regenerative Medicine is developing new tools to effectively command 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) tin be targeted to prevent the circuitous 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 every bit neurodegenerative or neuroinflammatory as well as those having an oncogenic footing.

    Efforts are directed at agreement the physiological and pathophysiological consequences of a family of G poly peptide-coupled receptors (protease-activated receptors, or PARs), and determining whether PARs or the proteases that actuate them can be targeted therapeutically to forestall pathogenesis and to promote CNS plasticity and repair to better patient functional outcomes.

Methodologies

  • Deep encephalon stimulation for Alzheimer'due south illness. Anecdotal and initial trial reports apropos deep brain stimulation (DBS) to the fornix and hypothalamus have been associated with improvement in retentivity function and reductions in expected cognitive decline in patients with early on Alzheimer'southward affliction. The fornix constitutes the major inflow and output pathway from the hippocampus and medial temporal lobe.

    Mayo researchers accept 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 cerebral pass up. 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 immature age may be associated with subsequently problems, such as learning disabilities and attention-deficit/hyperactivity disorder. Researchers in the Center for Regenerative Medicine are working on a large project involving the detailed testing of 1,000 children to try to better ascertain what injury (if whatever) may be associated with coldhearted exposure. This information will be of import to encounter if this is really a problem in clinical practice, and if so, to change do to minimize issues.

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

  • Neurogenesis. Past increasing the agreement of the molecular targets involved in regulation of developed hippocampal neurogenesis (neuron generation) and related behavioral responses altered in neuropathological conditions, scientists can study underlying cellular and molecular mechanisms that regulate the product, maturation and integration of new neurons in the circuitry, and how aberrant neurogenesis plays a role in affliction 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 handling systems and clinically approved medication that tin can allow dictation of neuronal development in the correct management. The long-term goal is to harness the regenerative capacity of adult neurogenesis toward an optimal clinical issue and improved handling options for brain disorders.

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

    By developing treatment approaches that atomic number 82 to improved function and independence, researchers in the Center for Regenerative Medicine promote the adaptive regenerative changes in encephalon function that make this improved behavioral functioning possible.

  • Transduction mechanisms mediating bidirectional nervus growth. Cues released from the breakdown of myelin later on injury in the brain and spinal cord may act equally chemorepellents and inhibit axon extension, which limits functional recovery. In contrast, positive cues such every bit neurotrophins tin 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 bespeak transduction mechanisms by which nerve growth cones discover 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 enquiry goal is to define mechanisms for priming and guiding regenerating axons to appropriate synaptic targets to complete functional circuits.

More than information

Neuroregenerative Medicine at Mayo Clinic (PDF)