Epigenetics of neural repair following spinal cord injury.

Spinal cord injury results from an insult inflicted on the spinal cord that usually encompasses its 4 major functions (motor, sensory, autonomic, and reflex). The type of deficits resulting from spinal cord injury arise from primary insult, but their long-term severity is due to a multitude of pathophysiological processes during the secondary phase of injury. The failure of the mammalian spinal cord to regenerate and repair is often attributed to the very feature that makes the central nervous system special-it becomes so highly specialized to perform higher functions that it cannot effectively reactivate developmental programs to re-build novel circuitry to restore function after injury.

Olfactory ensheathing cells promote corticospinal axonal outgrowth by a L1 CAM-dependent mechanism.

Olfactory ensheathing cells (OECs) support the ability of the olfactory neuraxis to continually retarget within the mature central nervous system. This has led many groups to transplant OECS into the lesioned rodent spinal cord (SCd) in vivo, with variable degrees of anatomical, physiological, and behavioral success. Some of the most conflicting results in OEC transplantation have come from the corticospinal tract (CST) which has shown a relatively poor regeneration response.

HDAC inhibitors dysregulate neural stem cell activity in the postnatal mouse brain.

The mammalian central nervous system (CNS) undergoes significant expansion postnatally, producing astrocytes, oligodendrocytes and inhibitory neurons to modulate the activity of neural circuits. This is coincident in humans with the emergence of pediatric epilepsy, a condition commonly treated with valproate/valproic acid (VPA), a potent inhibitor of histone deacetylases (HDACs). The sequential activity of specific HDACs, however, may be essential for the differentiation of distinct subpopulations of neurons and glia.

SPARC regulates microgliosis and functional recovery following cortical ischemia.

Secreted protein acidic rich in cysteine (SPARC) is a matricellular protein that modulates the activity of growth factors, cytokines, and extracellular matrix to play multiple roles in tissue development and repair, such as cellular adhesion, migration, and proliferation. Throughout the CNS, SPARC is highly localized in mature ramified microglia, but its role in microglia--in development or during response to disease or injury--is not understood. In the postnatal brain, immature amoeboid myeloid precursors only induce SPARC expression after they cease proliferation and migration, and transform into mature, ramified resting microglia.

Fibroblast growth factor signaling regulates neurogenesis at multiple stages in the embryonic olfactory epithelium.

Lifelong neurogenesis in the mouse olfactory epithelium (OE) is regulated by the response of stem/progenitor cells to local signals, but embryonic and adult OE progenitors appear to be quite different--with potentially different mechanisms of regulation. A recently identified progenitor unique to embryonic OE--the nestin+ radial glial-like progenitor--precedes some Mash1+ progenitors in the olfactory receptor neuron (ORN) lineage, which then gives rise to immediate neuronal precursors and immature ORNs. Neurogenic drive at each stage is governed largely by exogenous factors.

SPARC-like 1 (SC1) is a diversely expressed and developmentally regulated matricellular protein that does not compensate for the absence of SPARC in the CNS.

SPARC-like 1 (SC1) is a member of the SPARC family of matricellular proteins that has been implicated in the regulation of processes such as cell migration, proliferation, and differentiation. Here we show that SC1 exhibits remarkably diverse and dynamic expression in the developing and adult nervous system. During development, SC1 localizes to radial glia and pial-derived structures, including the vasculature, choroid plexus, and pial membranes.

Adult spinal cord radial glia display a unique progenitor phenotype.

Radial glia (RG) are primarily embryonic neuroglial progenitors that express Brain Lipid Binding Protein (Blbp a.k.a.

Combination of olfactory ensheathing cells with local versus systemic cAMP treatment after a cervical rubrospinal tract injury.

The failure of CNS axons to regenerate following traumatic injury is due in part to a growth-inhibitory environment in CNS as well as a weak intrinsic neuronal growth response. Olfactory ensheathing cell (OECs) transplants have been reported to create a favorable environment promoting axonal regeneration, remyelination, and functional recovery after spinal cord injury. However, in our previous experiments, OEC transplants failed to promote regeneration of rubrospinal axons through and beyond the site of a dorsolateral funiculus crush in rats.

MBD2 and MeCP2 regulate distinct transitions in the stage-specific differentiation of olfactory receptor neurons.

DNA methylation-dependent gene silencing is initiated by DNA methyltransferases (DNMTs) and mediated by methyl-binding domain proteins (MBDs), which recruit histone deacetylases (HDACs) to silence DNA, a process that is essential for normal development. Here, we show that the MBD proteins MBD2 and MeCP2 regulate distinct transitional stages of olfactory receptor neuron (ORN) differentiation in vivo. Mbd2 null progenitors display enhanced proliferation, recapitulated by HDAC inhibition, and Mbd2 null ORNs have a decreased lifespan.

Epigenetic regulation of nervous system development by DNA methylation and histone deacetylation.

Alterations in the epigenetic modulation of gene expression have been implicated in several developmental disorders, cancer, and recently, in a variety of mental retardation and complex psychiatric disorders. A great deal of effort is now being focused on why the nervous system may be susceptible to shifts in activity of epigenetic modifiers. The answer may simply be that the mammalian nervous system must first produce the most complex degree of developmental patterning in biology and hardwire cells functionally in place postnatally, while still allowing for significant plasticity in order for the brain to respond to a rapidly changing environment.

Health-related quality of life, treatment adherence, symptom experience and depression in adolescent renal transplant patients.

Few studies comprehensively assessed psychological and behavioral functioning in adolescent kidney transplant patients. The purpose of this cross-sectional study was to evaluate depression, QOL, treatment adherence and presence of side effects from the perspective of the patient and his parents, and to compare scores with norm data. All patients (age 10-18 yr) and their parents completed the following instruments: KIDSCREEN-27 (QOL), a treatment adherence interview, the MTSOSD-59R (side effects) and the Beck Depression Inventory (depression).

Corticospinal neurons respond differentially to neurotrophins and myelin-associated glycoprotein in vitro.

Elucidating the mechanisms that regulate the survival and outgrowth of corticospinal tract (CST) neurons and other CNS tracts will be a key component in developing novel approaches for the treatment of central nervous system (CNS) disorders, including stroke, spinal cord injury (SCI), and motor neuron disease (MND). However, the in vivo complexities of these diseases make a systematic evaluation of potential therapeutics that directly affect corticospinal regeneration or survival very challenging. Here, we use Thy1.

Undesired effects of a combinatorial treatment for spinal cord injury--transplantation of olfactory ensheathing cells and BDNF infusion to the red nucleus.

Transplantations of olfactory ensheathing cells (OECs) have been reported to promote axonal regeneration and functional recovery after spinal cord injury, but have demonstrated limited growth promotion of rat rubrospinal axons after a cervical dorsolateral funiculus crush. Rubrospinal neurons undergo massive atrophy after cervical axotomy and show only transient expression of regeneration-associated genes. Cell body treatment with brain-derived neurotrophic factor (BDNF) prevents this atrophy, stimulates regeneration-associated gene expression and promotes regeneration of rubrospinal axons into peripheral nerve transplants.

Histone deacetylases 1 and 2 are expressed at distinct stages of neuro-glial development.

The deacetylation of histone proteins, catalyzed by histone deacetylases (HDACs), is a common epigenetic modification of chromatin, associated with gene silencing. Although HDAC inhibitors are used clinically to treat nervous system disorders, such as epilepsy, very little is known about the expression pattern of the HDACs in the central nervous system. Identifying the cell types and developmental stages that express HDAC1 and HDAC2 within the brain is important for determining the therapeutic mode of action of HDAC inhibitors, and evaluating potential side effects.

A novel embryonic nestin-expressing radial glia-like progenitor gives rise to zonally restricted olfactory and vomeronasal neurons.

Persistent neurogenesis is maintained throughout development and adulthood in the mouse olfactory epithelium (OE). Despite this, the identity and origin of different embryonic OE progenitors, their spatiotemporal induction and contribution to patterning during development, has yet to be delineated. Here, we show that the embryonic OE contains a novel nestin-expressing radial glia-like progenitor (RGLP) that is not found in adult OE, which is antigenically distinct from embryonic CNS radial glia.

Culturing olfactory ensheathing cells from the mouse olfactory epithelium.

Olfactory ensheathing cells (OECs) are not a class of stem cell, but they are a specialized and highly plastic glial cell that can continuously support the neurogenesis and axonal regeneration of olfactory receptor neurons. Because of this, they have been transplanted into sites of spinal cord injury to test their efficacy in promoting repair. They also have been demonstrated to have some ability to support the remyelination of demyelinated axons.

Olfactory ensheathing cells: isolation and culture from the neonatal olfactory bulb.

Olfactory ensheathing cells (OECs), which are glia from the olfactory system, have evolved as attractive candidates for transplant-mediated repair based on long-standing knowledge that the olfactory system is one of the only central nervous system tissues that can support neurogenesis throughout life. After injury and during normal cell turnover, the olfactory receptor neurons (ORNs) die, and new nerves are generated from putative stem cells in the olfactory epithelium. OECs, which reside throughout the olfactory system, guide the ORN axons as they travel through the olfactory mucosa (olfactory epithelium and lamina propria) and the cribriform plate, terminating in synapse formation in the usually nonpermissive environment of the olfactory bulb.

SPARC is expressed by macroglia and microglia in the developing and mature nervous system.

SPARC (secreted protein, acidic and rich in cysteine) is a matricellular protein that is highly expressed during development, tissue remodeling, and repair. SPARC produced by olfactory ensheathing cells (OECs) can promote axon sprouting in vitro and in vivo. Here, we show that in the developing nervous system of the mouse, SPARC is expressed by radial glia, blood vessels, and other pial-derived structures during embryogenesis and postnatal development.

Olfactory epithelium progenitors: insights from transgenic mice and in vitro biology.

The rodent olfactory epithelium (OE) is capable of prolonged neurogenesis, beginning at E10 in the embryo and continuing throughout adulthood. Significant progress has been made over the last 10 years in revealing the signals that drive induction, differentiation and survival of its Olfactory Receptor Neurons (ORNs). Our understanding of the identity of specific progenitors or precursors that respond to these signals is, however, less well developed, and the search is still on for the elusive, definitive multipotent neuro-glial OE "Stem cell".

Olfactory ensheathing cell transplantation following spinal cord injury: hype or hope?

Olfactory ensheathing cells (OECs) are unique glia found only in the olfactory system that retain exceptional plasticity, and support olfactory neurogenesis and the re-targeting across the PNS:CNS boundary in the olfactory system. Because they are also relatively accessible in an adult rodent or human, OECs have become a prime candidate for cell-mediated repair following a variety of CNS lesions. A number of different labs across the world have applied OECs prepared in many different ways in several different acute and chronic models of rodent SCI, some of which have suggested surprising degrees of functional recovery.

SPARC from olfactory ensheathing cells stimulates Schwann cells to promote neurite outgrowth and enhances spinal cord repair.

Olfactory ensheathing cells (OECs) transplanted into the lesioned CNS can stimulate reportedly different degrees of regeneration, remyelination, and functional recovery, but little is known about the mechanisms OECs may use to stimulate endogenous repair. Here, we used a functional proteomic approach, isotope-coded affinity tagging and mass spectrometry, to identify active components of the OEC secreteome that differentially stimulate outgrowth. SPARC (secreted protein acidic rich in cysteine) (osteonectin) was identified as an OEC-derived matricellular protein that can indirectly enhance the ability of Schwann cells to stimulate dorsal root ganglion outgrowth in vitro.

Olfactory ensheathing cells do not exhibit unique migratory or axonal growth-promoting properties after spinal cord injury.

Olfactory ensheathing cells (OECs) have been reported to migrate long distances and to bridge lesion sites, guiding axonal regeneration after spinal cord injury (SCI). To understand mechanisms of OEC migration and axonal guidance, we injected lamina propria OECs 1 mm rostral and caudal to C4 SCI sites. One month later, OECs formed an apparent migrating cell tract continuously extending from the injection site through the lesion, physically bridging the lesion.

Notch 2 and Notch 1/3 segregate to neuronal and glial lineages of the developing olfactory epithelium.

The murine olfactory epithelium (OE) generates olfactory receptor neurons (ORNs) throughout development and into adulthood, but only a few of the factors regulating olfactory neuro- and glio-genesis have been delineated. Notch receptors maintain CNS neuronal progenitors and drive glial differentiation, and the Notch effectors Hes 1 and 5 are expressed in the OE, but the Notch receptors that stimulate Hes gene activation in defined lineages during OE development have not been determined. Here, we first use RT-PCR to reveal which Notch receptors and ligands are expressed in the developing and adult OE.

Lamina propria and olfactory bulb ensheathing cells exhibit differential integration and migration and promote differential axon sprouting in the lesioned spinal cord.

Olfactory bulb-derived (central) ensheathing cell (OB OEC) transplants have shown significant promise in rat models of spinal cord injury, prompting the use of lamina propria-derived (peripheral) olfactory ensheathing cells (LP OECs) in both experimental and clinical trials. Although derived from a common embryonic precursor, both sources of OECs reside in different nervous system compartments postnatally, and their ability to promote regeneration and efficacy after transplantation may differ depending on both their source and mode of transplantation. Here, we have purified green fluorescent protein-expressing LP and OB OECs, assayed their biological differences in vitro, and transplanted them acutely either directly into or rostral and caudal to a dorsolateral funiculus crush.

Stage-specific induction of DNA methyltransferases in olfactory receptor neuron development.

DNA methylation-dependent gene silencing, mediated by DNA methyltransferases (DNMTs), is essential for normal mammalian development and its dysregulation has been implicated in neurodevelopmental disorders. Despite this, little is known about DNMTs in the developing or mature nervous system. Here, we show that DNMT1, 3a and 3b are expressed at discrete developmental stages in the olfactory neuron lineage, coincident with key shifts in developmental gene expression.