Biomedical subjects

Thomas A Reh

Publications and source records attributed to Thomas A Reh.

26 records · Page 2Linked to original sources

PubMed2004

BMP4 and CNTF are neuroprotective and suppress damage-induced proliferation of Müller glia in the retina.

In response to acute damage, Müller glia in the chicken retina have been shown to be a source of proliferating progenitor-like cells. The secreted factors and signaling pathways that regulate this process remain unknown. The purpose of this study was to test whether secreted factors, which are known to promote glial differentiation during development, regulate the ability of Müller glia to proliferate and become retinal progenitors in response to acute damage in mature retina. We made intraocular injections of BMP4, BMP7, EGF, NGF, BDNF, or CNTF before or after a single, toxic dose of N-methyl-d-aspartate (NMDA) and assayed for proliferating progenitor-like cells within the retina. We found that injections of BMP4, BMP7, or CNTF, but not EGF, NGF, or BDNF, before NMDA treatment reduced the number of Müller glia that proliferated and gave rise to progenitor-like cells. CNTF and BMP4, but not NGF or BDNF, greatly reduced the number of cells destroyed by toxin treatment indicating that these factors protect retinal neurons from a severe excitotoxic insult. Injections of CNTF 5 days before NMDA treatment prevented neurotoxin-induced cell death and Müller glial proliferation, while injections of BMP4 had no protective effect. In addition, CNTF injected after NMDA treatment suppressed glial proliferation, while BMP4 did not. We conclude that BMP4 and CNTF, when applied before a toxic insult, act as neuroprotective agents and likely suppress the proliferative response of Müller glia to retinal damage by attenuating the retinal damage; protecting bipolar and amacrine neurons from NMDA-induced cell death. When applied after a toxic insult, CNTF suppressed glial proliferation independent of levels of retinal damage.

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PubMed2004

Retinal stem cells and regeneration.

The optic vesicle gives rise to several very different epithelial tissues, including the neural retina, the pigmented epithelium, the iris, the ciliary epithelium of the ciliary body and the optic stalk. Retinal regeneration can arise from several different cellular sources; in some species, the process involves interconversion, or transdifferentiation, among cells of the different tissue types. Therefore, prior to a discussion of retinal regeneration, we will briefly discuss current knowledge about the influence of signaling molecules in cell fate determination in ocular tissues. Next, we will detail the evidence for neurogenesis in the mature retina. Lastly, we will describe various types of regenerative phenomena that occur in the retina, from complete regeneration of functional retina in fish and amphibians, to the more limited neuronal production that occurs in avian and mammalian retinas.

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PubMed2003

Growth factors induce neurogenesis in the ciliary body.

The ciliary body of the eye is a nonneural tissue that is derived from the anterior rim of the optic cup, an extension of the neural tube. This tissue normally does not contain neurons and functions to produce components of the aqueous humor. We found that intraocular injections of insulin, EGF, or FGF2 stimulate NPE cells to proliferate and differentiate into neurons. These growth factors had region-specific effects along the radial axis of the ciliary body, with insulin and EGF stimulating proliferation of NPE cells close to the retina, while FGF2 stimulated the proliferation of NPE cells further toward the lens. Similar region-specific effects were observed for accumulations of neurons in the NPE in response to injections of different growth factors. The neurons derived from NPE cells express neurofilament, beta3 tubulin, RA4, calretinin, Islet1, or Hu, and a few produced long axonal projections, several millimeters in length that extend across the ciliary body. Our results suggest that the ciliary body has the capacity to generate retinal neurons, but normally neurogenesis is actively inhibited.

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PubMed2003

Potential of Müller glia to become neurogenic retinal progenitor cells.

The possibility of neural regeneration has gained credence with the identification of neural stem cells seeded within different regions of the adult central nervous system (CNS). Recently, this possibility has received an additional boost from reports that glia, the support cells of the CNS, might provide a source of neural regeneration. We review some of our findings that Müller glia in the chicken retina are a source of proliferating progenitors that can generate neurons. These Müller cells are fully differentiated glial cells that serve functions ascribed to this cell type. In response to damage or exogenous growth factors, Müller glia dedifferentiate, proliferate, express combinations of transcription factors normally expressed by embryonic retinal progenitors, and produce new neurons and glia. In light of these data, the potential of Müller glia as a source of neural regeneration in the retina of nonavian species, namely humans, seems an avenue of investigation that warrants serious consideration.

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PubMed2002

Exogenous growth factors stimulate the regeneration of ganglion cells in the chicken retina.

Recent reports have found that the posthatch chicken retina has the capacity for neuronal regeneration. The purpose of this study was to test whether the types of cells destroyed by neurotoxic lesions influence the types of cells that are regenerated, and whether exogenous growth factors stimulate neural regeneration in the chicken retina. N-methyl-D-aspartate (NMDA) was used to destroy amacrine and bipolar cells; kainate was used to destroy bipolar, amacrine, and ganglion cells; colchicine was used to selectively destroy ganglion cells. Following toxin-induced damage, bromo-deoxyuridine was used to label proliferating cells. In some animals, growth factors were injected into the vitreous chamber of the eye. We found that the proliferation of cells within the retina was stimulated by toxin-induced cell loss, and by insulin and FGF2. After either kainate- or colchicine-induced retinal damage, some of the newly generated cells expressed markers and had the morphology of ganglion cells. The combination of insulin and FGF2 stimulated the regeneration of ganglion cells in kainate- and colchicine-treated retinas. We conclude that exogenous growth factors can be used to stimulate neural regeneration in the retina. We propose that the type of neuron destroyed in the retina may allow or promote the regeneration of that neuronal type.

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PubMed2002

Insulin and fibroblast growth factor 2 activate a neurogenic program in Müller glia of the chicken retina.

We have reported previously that neurotoxic damage to the chicken retina causes Müller glia to dedifferentiate, proliferate, express transcription factors common to retinal progenitors, and generate new neurons and glia, whereas the majority of newly produced cells remain undifferentiated (Fischer and Reh, 2001). Because damaged retinal cells have been shown to produce increased levels of insulin-related factors and FGFs, in the current study we tested whether intraocular injections of growth factors stimulate Müller glia to proliferate and produce new neurons. We injected growth factors and bromodeoxyuridine into the vitreous chamber of the eyes of chickens and assayed for changes in glial phenotype and proliferation within the retina. Although insulin or FGF2 alone had no effect, the combination of insulin and FGF2 caused Müller glia to coexpress transcription factors common to retinal progenitors (Pax6 and Chx10) and initiated a wave of proliferation in Müller cells that began at the retinal margin and spread into peripheral regions of the retina. Most of the newly formed cells remain undifferentiated, expressing Pax6 and Chx10, whereas some differentiate into Müller glia, and a few differentiate into neurons that express the neuronal markers Hu or calretinin. There was no evidence of retinal damage in eyes treated with insulin and FGF2. We conclude that the combination of insulin and FGF2 stimulated Müller glia to dedifferentiate, proliferate, and generate new neurons. These findings imply that exogenous growth factors might be used to stimulate endogenous glial cells to regenerate neurons in the CNS.

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PubMed2002

Neurodevelopmental control by thyroid hormone receptors.

Recent studies have provided insights into the neurodevelopmental functions of thyroid hormone signaling. The nuclear thyroid hormone receptors (TRs) are ligand-activated transcription factors and a variety of TR isotypes, generated by two genes, mediate distinct processes. In addition, deiodinase enzymes that regulate levels of the main active form of thyroid hormone, T3, are likely to cooperate closely with TRs in specifying a localized and timely response to thyroid hormones in target tissues. Some of the most sensitive processes controlled by these pathways are in the auditory and visual sensory systems.

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PubMed2002

Exogenous growth factors induce the production of ganglion cells at the retinal margin.

Neural progenitors at the retinal margin of the post-hatch chicken normally produce amacrine and bipolar cells, but not photoreceptor or ganglion cells. The purpose of this study was to test whether exogenous growth factors influence the types of cells produced by progenitors at the retinal margin. We injected insulin, FGF2 or a combination of insulin and FGF2 into the vitreous chamber of post-hatch chickens. To assay for growth factor-induced changes at the retinal margin, we used in situ hybridization and immunocytochemistry on cryosections. One day after the final injection, we found that insulin alone stimulated the addition of cells to the retinal margin, but this was not further increased when FGF2 was applied with insulin. Insulin alone increased the number of cells in the progenitor zone that expressed neurofilament, and this was further increased when FGF2 was applied with insulin. These neurofilament-expressing cells in the progenitor zone included differentiating neurons that expressed Islet1 or Hu. Four days after the final dose of growth factor, we found that the production of ganglion cells was induced by co-injection of insulin and FGF2, but not by either insulin or FGF2 alone. We conclude that the types of cells produced by progenitors at the retinal margin can be altered by exogenous growth factors and that normally the microenvironment imposes limitations on the types of neurons produced.

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