Biomedical subjects

Robert H Miller

Publications and source records attributed to Robert H Miller.

At least 19 recordsLinked to original sources

PubMed2007

NGF regulates the expression of axonal LINGO-1 to inhibit oligodendrocyte differentiation and myelination.

Neurons and glia share a mutual dependence in establishing a functional relationship, and none is more evident than the process by which axons control myelination. Here, we identify LRR and Ig domain-containing, Nogo receptor-interacting protein (LINGO-1) as a potent axonal inhibitor of oligodendrocyte differentiation and myelination that is regulated by nerve growth factor and its cognate receptor TrkA in a dose-dependent manner. Whereas LINGO-1 expressed by oligodendrocyte progenitor cells was previously identified as an inhibitor of differentiation, we demonstrate that axonal expression of LINGO-1 inhibits differentiation with equal potency. Disruption of LINGO-1 on either cell type is sufficient to overcome the inhibitory action and promote differentiation and myelination, independent of axon diameter. Furthermore, these results were recapitulated in transgenic mice overexpressing the full length LINGO-1 under the neuronal promoter synapsin. Myelination was greatly inhibited in the presence of enforced axonal LINGO-1. The implications of these results relate specifically to the development of potential therapeutics targeting extrinsic growth factors that may regulate the axonal expression of modulators of oligodendrocyte development.

Animals↗

PubMed2006

Human mesenchymal stem cells signals regulate neural stem cell fate.

Neural stem cells (NSCs) differentiate into neurons, astrocytes and oligodendrocytes depending on their location within the central nervous system (CNS). The cellular and molecular cues mediating end-stage cell fate choices are not completely understood. The retention of multipotent NSCs in the adult CNS raises the possibility that selective recruitment of their progeny to specific lineages may facilitate repair in a spectrum of neuropathological conditions. Previous studies suggest that adult human bone marrow derived mesenchymal stem cells (hMSCs) improve functional outcome after a wide range of CNS insults, probably through their trophic influence. In the context of such trophic activity, here we demonstrate that hMSCs in culture provide humoral signals that selectively promote the genesis of neurons and oligodendrocytes from NSCs. Cell-cell contacts were less effective and the proportion of hMSCs that could be induced to express neural characteristics was very small. We propose that the selective promotion of neuronal and oligodendroglial fates in neural stem cell progeny is responsible for the ability of MSCs to enhance recovery after a wide range of CNS injuries.

Animals↗

PubMed2006

Identification and characterization of mouse cochlear stem cells.

Genetic, noise- and drug-induced loss of hair cells in the mouse and human cochlea leads to permanent hearing loss due to lack of regeneration of hair cells, which may be due to reduced numbers or loss of the regenerative ability of stem cells in the adult cochlea. We hypothesized that the mouse neonate cochlea harbors stem cells capable of differentiating into hair cells. Cells from the primary neonate cochlear culture began to proliferate and formed floating spheres after 14 days in vitro (DIV). By comparison, spheres from the primary culture of the cortex were observed after 7 DIV. Cochlear sphere cells could be passaged and the new spheres were observed after 7 DIV. Cochlear sphere cells were capable of differentiating into astrocytes and oligodendrocytes, but not neurons under the conditions tested. Cochlear sphere cells expressed Sox2 and Myo7a, but failed to show markers that are expressed exclusively in mature cochlear tissue, while cells from cortex spheres expressed Sox2 and Otx2, but not Myo7a. Our results show that cochleae from neonatal mice harbor cells capable of forming spheres and cells from these spheres appear to be better endowed to become hair cells.

Age Factors↗

PubMed2006

Specification of optic nerve oligodendrocyte precursors by retinal ganglion cell axons.

Cell fate commitment in the developing CNS frequently depends on localized cell-cell interactions. In the avian visual system the optic nerve oligodendrocytes are derived from founder cells located at the floor of the third ventricle. Here we show that the induction of these founder cells is directly dependent on signaling from the retinal ganglion cell (RGC) axons. The appearance of oligodendrocyte precursor cells (OPCs) correlates with the projection of RGC axons, and early eye removal dramatically reduces the number of OPCs. In vitro signaling from retinal neurites induces OPCs in responsive tissue. Retinal axon induction of OPCs is dependent on sonic hedgehog (Shh) and neuregulin signaling, and the inhibition of either signal reduces OPC induction in vivo and in vitro. The dependence of OPCs on retinal axonal cues appears to be a common phenomenon, because ocular retardation (or(J)) mice lacking optic nerve have dramatically reduced OPCs in the midline of the third ventricle.

Animals↗

PubMed2006

Building bridges with astrocytes for spinal cord repair.

Simultaneous suppression of glial scarring and a general enhancement of axonal outgrowth has now been accomplished in an adult rat model of spinal cord transection. Transplantation of a novel astrocyte cell type derived from glial-restricted precursors in vitro raise the eventual possibility of cellular therapy for spinal cord injury.

Animals↗

PubMed2006

The promise of stem cells for neural repair.

The realization that the adult nervous system develops from multipotential stem cells and that cells with stem-like properties are retained in the adult CNS has provoked an intense search for ways to utilize their potential for therapeutic treatments of multiple neurological disorders. Transplantation of neural stem cells or more restricted progenitors to replace cells lost to injury or disease may facilitate functional recovery in a spectrum of neurological disorders. Alternatively, expansion and recruitment of endogenous progenitors may be effective in treating widespread cell loss in the adult CNS. A major challenge to the development of effective stem cell therapies is to direct the fate of the newly generated cells to specifically replace those lost to disease. Insights from developmental research are providing molecular targets for regulating the differentiation of neural stem cells and their progeny in areas of injury to the adult CNS. Given the commonality of processes mediating the assembly of multicellular systems, the approaches developed in the CNS will likely be applicable for selective cell replacement in the auditory system.

Animals↗

PubMed2006

Netrin-1 is required for the normal development of spinal cord oligodendrocytes.

Successful CNS myelination is dependent on the correct localization of oligodendrocytes and their interactions with adjacent axons. In the spinal cord, oligodendrocyte precursors originate at the ventral midline and subsequently migrate to the white matter where they mature. In vitro studies suggest this dispersal is mediated by the guidance molecule netrin-1. Here, we show that in the spinal cord of netrin-1 mutant mice, oligodendrocyte precursors failed to disperse from the ventral midline as a consequence of a lack of polarization and directional migration. The lack of netrin-1 also resulted in an overall reduction of oligodendrocyte lineage cells that was independent of the failure of initial dispersal. Oligodendrocyte precursors injected into presumptive white matter underwent extensive radial migration and expansion in wild-type but not netrin-1 mutant hosts. These data indicate that netrin-1 is crucial for both the initial dispersal of spinal cord oligodendrocyte precursors and their subsequent development in the presumptive white matter.

Animals↗

PubMed2006

Intrinsic and extrinsic inhibition of oligodendrocyte development by rat retina.

Cell patterning in the vertebrate CNS reflects the combination of localized cell induction, migration and differentiation. A striking example of patterning is the myelination of visual system. In many species, retinal ganglion cell axons are myelinated in the optic nerve but are unmyelinated in the retina. Here, we confirm that rat and mouse retina lack oligodendrocytes and their precursors and identify multiple mechanisms that might contribute to their absence. Soluble cues from embryonic retina inhibit the induction of oligodendrocytes from neural stem cells and their differentiation from optic nerve precursors. This inhibition is mediated by retinal-derived BMPs. During development BMPs are expressed in the retina and addition of the BMP antagonist Noggin reversed retinal inhibition of oligodendrocyte development. The lack of retinal oligodendrocytes does not simply reflect expression of BMPs, since no oligodendrocytes or their precursors developed when embryonic retinal cells were grown in the presence of Noggin and/or inductive cues such as Shh and IGF-1. Similarly, injection of Noggin into the postnatal rat eye failed to induce oligodendrocyte differentiation. These data combined with the proposed inhibition of OPC migration by molecules selectively expressed at the nerve retina junction suggest that multiple mechanisms combine to suppress retinal myelination during development.

Animals↗

PubMed2006

Alterations in the oligodendrocyte lineage, myelin, and white matter in adult mice lacking the chemokine receptor CXCR2.

Oligodendrocyte precursor cell (OPC) proliferation and migration are critical for the development of myelin in the central nervous system (CNS). Previous studies showed that localized expression of the chemokine CXCL1 signals through the receptor CXCR2 to inhibit the migration and enhance the proliferation of spinal cord OPCs during development. Here, we report structural and functional alterations in the adult CNS of Cxcr2-/- mice. In Cxcr2-/- adult mice, we observed regional alterations in the density of oligodendrocyte lineage cells in Cxcr2-/- adult mice, with decreases in the cortex and anterior commissure but increases in the corpus callosum and spinal cord. An increase in the density and arborization of spinal cord NG2 positive cells was also observed in Cxcr2-/- adult mice. Compared with wild-type (WT) littermates, Cxcr2-/- mice exhibited a significant decrease in spinal cord white matter area, reduced thickness of myelin sheaths, and a slowing in the rate of central conduction of spinally elicited evoked potentials without significant changes in axonal caliber or number. Biochemical analyses showed decreased levels of myelin basic protein (MBP), proteolipid protein (PLP), and glial fibrillary acidic protein (GFAP). In vitro studies showed reduced numbers of differentiated oligodendrocytes in Cxcr2-/- spinal cord cultures. Together, these findings indicate that the chemokine receptor CXCR2 is important for the development and maintenance of the oligodendrocyte lineage, myelination, and white matter in the vertebrate CNS.

Animals↗

PubMed2005

Endogenous stem cell proliferation after central nervous system injury: alternative therapeutic options.

The continuous regeneration of glial cells arising from endogenous stem cell populations in the central nervous system (CNS) occurs throughout life in mammals. In the ongoing research to apply stem cell therapy to neurological diseases, the capacity to harness the multipotential ability of endogenous stem cell populations has become apparent. Such cell populations proliferate in response to a variety of injury states in the CNS, but in the absence of a supportive microenvironment they contribute little to any significant behavioral recovery. In the authors' laboratory and elsewhere, recent research on the regenerative potential of these stem cells in disease states such as spinal cord injury has demonstrated that the cells' proliferative potential may be greatly upregulated in response to appropriate growth signals and exogenously applied trophic factors. Further understanding of the potential of such multipotent cells and the mechanisms responsible for creating a favorable microenvironment for them may lead to additional therapeutic alternatives in the setting of neurological diseases. These therapies would require no exogenous stem cell sources and thus would avoid the ethical and moral considerations regarding their use. In this review the authors provide a brief overview of the enhancement of endogenous stem cell proliferation following neurological insult.

Animals↗

PubMed2005

The ErbB4 neuregulin receptor mediates suppression of oligodendrocyte maturation.

Neuregulin is required for proper oligodendrocyte development, but which receptors are involved and whether neuregulin promotes or inhibits maturation remain controversial. To assess the roles of the neuregulin receptor ErbB4 in oligodendrocyte development, we examined oligodendrocyte initiation and maturation in cultures derived from erbB4 knock-out mice and rat spinal cord in the presence of neutralizing erbB4 antibodies. No differences in the development of O4+ oligodendrocytes were detected in the presence or absence of erbB4 signaling. All four epidermal growth factor receptor family members were detected in the ventral neural tube at approximately the time of initial oligodendrocyte development, consistent with redundancy in neuregulin receptor signaling at the onset of oligodendrocyte development. In contrast, greater numbers of differentiated (monoclonal antibody O1+) oligodendrocytes developed in neural tube explants from erbB4(-/-) mice than either erbB4(+/+) or erbB4(+/-) littermates as well as in cultures treated with anti-erbB4. These data indicate that ErbB4 is not required for oligodendrocyte development and, in fact, inhibits oligodendrocyte lineage maturation. Together with previous studies, these data suggest a model in which early oligodendrocyte lineage development is regulated by promiscuous neuregulin receptor signaling, but subsequent lineage progression occurs through a balance of receptor-specific promotion or inhibition of maturation.

Animals↗

PubMed2005

LINGO-1 negatively regulates myelination by oligodendrocytes.

The control of myelination by oligodendrocytes in the CNS is poorly understood. Here we show that LINGO-1 is an important negative regulator of this critical process. LINGO-1 is expressed in oligodendrocytes. Attenuation of its function by dominant-negative LINGO-1, LINGO-1 RNA-mediated interference (RNAi) or soluble human LINGO-1 (LINGO-1-Fc) leads to differentiation and increased myelination competence. Attenuation of LINGO-1 results in downregulation of RhoA activity, which has been implicated in oligodendrocyte differentiation. Conversely, overexpression of LINGO-1 leads to activation of RhoA and inhibition of oligodendrocyte differentiation and myelination. Treatment of oligodendrocyte and neuron cocultures with LINGO-1-Fc resulted in highly developed myelinated axons that have internodes and well-defined nodes of Ranvier. The contribution of LINGO-1 to myelination was verified in vivo through the analysis of LINGO-1 knockout mice. The ability to recapitulate CNS myelination in vitro using LINGO-1 antagonists and the in vivo effects seen in the LINGO-1 knockout indicate that LINGO-1 signaling may be critical for CNS myelination.

Animals↗

PubMed2005

Dorsally derived oligodendrocytes come of age.

While oligodendrocyte precursors have previously been localized to the ventral midline, two papers in this issue of Neuron (Cai et al. and Vallstedt et al.) provide compelling evidence for a second dorsal origin of oligodendrocyte precursors in the spinal cord and hindbrain. These cells share expression of the PDGFalpha receptor and Olig2 with their ventral counterparts but differ in the requirement for Nkx6 and hedgehog signaling.

Animals↗

PubMed2005

Developmental changes induced by graded prenatal systemic hypoxic-ischemic insults in rats.

In infants, a common consequence of systemic perinatal insults is disruption of neonatal brain development. Such insults can cause cerebral palsy, cognitive delay, epilepsy and other chronic neurologic deficits in children. The mechanisms underlying disruption of brain development after perinatal insults are poorly defined. To mimic human systemic insults, a transient prenatal hypoxic-ischemic insult model was developed in rodents. Ischemic animals showed reproducible histological lesions including oligodendrocyte loss, gliosis, and axonal disruption. Ischemic animals displayed persistent postnatal loss of oligodendrocyte lineage cells and cortical neurons, decreased cell proliferation, increased cell death, elevated pro-inflammatory cytokine levels, and impaired motor skills as young adults. Progressive ischemic intervals produced a graded pattern of injury. This systemic rodent prenatal hypoxic-ischemic insult accurately models human perinatal brain injury in several important criteria, including functional association of altered brain development with motor delay, and consequently provides novel insights into the pathogenesis of human perinatal brain insults.

Animals↗

PubMed2004

Emerging roles for bone morphogenetic proteins in central nervous system glial biology.

Bone morphogenetic proteins, members of the TGFbeta superfamily have been implicated in a variety of roles in the developing and mature nervous system. These divergent functions are a reflection of the closely defined spatial and temporal expression of BMPs in the CNS, and the potential interactions of the BMP signaling pathway with the STAT and MAP kinase pathways. In this review we discuss the roles of BMPs in early patterning of the CNS, determination of neural cell fate, and regulation of oligodendrocyte maturation during CNS development. Additional functions for members of the TGFbeta superfamily in CNS injury responses are emerging suggesting these molecules represent useful targets for manipulating neural responses to CNS insults.

Animals↗

PubMed2004

Patterning of spinal cord oligodendrocyte development by dorsally derived BMP4.

Oligodendrocyte precursors (OPCs) initially arise in the motor neuron domain of the ventral ventricular zone of the developing spinal cord. After dispersal throughout gray and white matter, OPCs differentiate in a characteristic ventral to dorsal sequence. The spatial localization of OPC induction is in part a result of both positive local sonic hedgehog signaling and dorsally derived inhibitory cues. One component of dorsal inhibitory signals seems to be members of the transforming growth factor beta (TGFbeta) superfamily such as the bone morphogenetic proteins (BMPs). We show that during the initial appearance and subsequent maturation of OPCs, BMP4 was expressed specifically in the dorsal midline and its expression was correlated spatially and temporally with phospho-Smad 1+, BMP4-responsive cells. Implantation of sonic hedgehog (Shh)-coated beads adjacent to dorsal spinal cord in Xenopus embryos induced ectopic dorsal OPCs whereas BMP4-coated beads inhibited OPC appearance. More importantly, blocking endogenous dorsal BMP4 with anti-BMP4-coated beads locally induced ectopic OPCs. Similar results were obtained using soluble ligands on slice preparations of rodent spinal cord in vitro. In dissociated cell cultures of embryonic rat spinal cord, Shh and BMP4 had antagonistic effects on OPC development and the sensitivity of oligodendrocyte lineage cells to BMP4 increased with maturation. These data suggest that BMP4 contributes to the pattern of spinal cord oligodendrogenesis by regulating both induction and maturation of spinal cord OPCs.

Animals↗

PubMed2004

Physician use of IT: results from the Deloitte Research Survey.

The authors analyzed 1,200 physician responses to a Deloitte Research/Fulcrum Analytics survey of office-based physician use of the Internet and other information technology (IT). Overall, the results suggest that 40 to 50 percent of all respondents are using, or are ready to use, IT for substantial clinical care. However, time and liability concerns about patient e-mail were pervasive across all IT user categories. The results also indicate that some public/private policies aimed at increasing physician IT use for clinical management should be tailored to specific segments of the physician IT user spectrum, rather than using a "one-size-fits-all" policy approach.

Adult↗

PubMed2004

Electronic medical records in solo/small groups: a qualitative study of physician user types.

BACKGROUND: There is growing recognition that physician use of electronic medical records (EMRs) is critical for improving quality of care in outpatient settings. METHODS: We inter-viewed EMR physician champions from 20 solo/small group practices to understand different types of EMR users and their EMR-related costs and benefits. RESULTS: Interviewees differed greatly in the EMR-related benefits they generated. These differences were associated with how they used the EMR, and the amount of effort they invested in making changes to complement EMR use. We defined five types of physician EMR users: Viewers, Basic Users, Strivers, Arrivers, and System Changers. The majority of interviewees were Strivers and Arrivers, physicians who have already invested substantial time in numerous process changes that help generate EMR-related benefits. CONCLUSIONS: Incentives and comprehensive support services for facilitating complementary process changes could be important for moving physicians from one user group to another. Additional research is needed to verify this user typology and to further define the relationship between user types and EMR-generated financial and quality benefits.

Ambulatory Care↗