Unit on Neuron-Glia Interactions in Retinal Disease
Wai T. Wong
Wai T. Wong, M.D., Ph.D.
The research focus of the unit is centered on discovering how intercellular interactions between retinal cells go awry in retinal diseases and relating these interactions with mechanisms of disease pathogenesis. Our group is also involved in clinical studies of retinal diseases, as well as in clinical trials evaluating new treatments of retinal diseases such as age-related macular degeneration (AMD) and diabetic retinopathy. Our overall goal is thus to translate discoveries on retinal cellular mechanisms to new therapeutic strategies that can be evaluated in clinical studies.
Our key areas of work are:
- Understanding the basic physiology of microglia in the retina:
Retinal microglia share many similarities with those found elsewhere in the CNS, but however, possess some distinguishing features in their morphology, distribution, and neighboring cells types that may relate to specialized functions. Unlike in the brain, ramified retinal microglia are arrayed in the inner retina in non-overlapping horizontal mosaic arrays with their processes are concentrated in the inner and outer plexiform layers in close proximity to retinal synapses. Interestingly, the outer retina, where photoreceptors and the retinal pigment epithelium (RPE) are located, is normally devoid of microglia coverage. Additionally, microglia are in proximity to, and interact with, specialized retinal cells types, such as Müller cells and RPE cells. We are interested in understanding the interactions that retinal microglia have with these specialized retinal cells in the endogenous functioning of the retina.
One significant physiological property of microglia of interest is their marked dynamism. Retinal microglia under normal conditions exhibit very rapid surveying movements in their processes that effectively cover the entire extracellular milieu. The functional significance of these movements is still not well understood and likely to be of functional importance. We are interested in understanding the dynamics and nature of this microglial behavior, how it is regulated, what other cell types are influenced by this movement, and the cellular consequences that result when this behavior is perturbed.
In our previous studies, we have characterized the nature of microglial dynamics in the retina under normal and injured conditions. We have also discovered that neuron-microglial chemokine signaling also plays a role in modulating in dynamics of microglial movement, in terms of both process movement and cellular migration. Neurotransmission, in particular, glutamatergic and GABAergic transmission, also appear to regulate in a reciprocal fashion, microglial dynamics, likely through ATP as an intermediary. Taken together, it is likely that microglial behavior is highly responsive to neuronal signals and is likely to have important functions related to neuronal function.
- Understanding alterations in intercellular interactions between microglia and other retinal cell types in retinal disease:
Microglia, under conditions of aging and in patients with AMD, translocate from the inner retina where they are normally found, to the subretinal space to come in close contact with photoreceptors and RPE cells. We are interested in the nature of microglia-RPE interactions and how their novel union under disease conditions may drive disease pathogenesis.
We have discovered using in vitro models that retinal microglia exert inductive influences on RPE cells that result in changes in structure, distribution, and gene expression that recapitulate some changes seen in RPE in AMD eyes. In particular, microglia induce increases in pro-inflammatory, chemotactic, and pro-angiogenic factors that are well-suited for fostering the formation of neovascular changes in "wet" AMD. Indeed, transplantation of exogenous retinal microglia into the subretinal space in an in vivo model was effective in significantly inducing the formation of choroidal neovascular membranes such as that seen in human disease.
In the future projects, we are interested in understanding the cellular events responsible for attracting microglia from the inner to the outer retina, and the activating influences on microglia in the subretinal space.
(left to right) Lian Zhao, Mausam Damani, Wai T. Wong, Minhua Wang, and Wenxin Ma
|Wai T. Wong, M.D., Ph.D.
|Wenxin Ma, M.D., Ph.D.||Scientist (Contractor)||firstname.lastname@example.org|
|Minhua Wang, Ph.D.||Postdoctoral Fellow (IRTA)||email@example.com|
|Lian Zhao, Ph.D.||Scientist (Contractor)||firstname.lastname@example.org|
|Anil Kumar, Ph.D.||Postdoctoral Fellow (IRTA)||email@example.com|
- Wong, W.T. Microglial Aging in the Healthy CNS: Phenotypes, Drivers, and Rejuvenation. Frontiers in Cellular Neuroscience, in press.
- Condren, A.B., Kumar, A., Mettu, P., Liang, K.J., Zhao, L., Tsai, J-Y., Fariss, R.N., Wong, W.T. Perivascular mural cells of the mouse choroid demonstrate morphological diversity that is correlated with vasoregulatory function. PLoS One, 2013;8(1):e53386.
- Ma, W., Coon, S., Zhao, L., Fariss, R.N., Wong, W.T. A2E accumulation influences retinal microglial activation and complement regulation. Neurobiology of Aging, 2013;34(3):943-60.
- Wang, M., Ma, W., Zhao, L., Fariss, R.N., Wong, W.T. Adaptive Muller Cell Responses to Microglial Activation Mediate Neuroprotection and Coordinate Inflammation in the Retina. Journal of Neuroinflammation, 2011;8:173.
- Cukras, C.A., Petrou, P., Chew, E.Y., Meyerle, C.B., Wong, W.T. Oral Minocycline for the Treatment of Diabetic Macular Edema (DME): Results of a Phase I/II Clinical Study. Investigative Ophthalmology and Visual Science, 2012;22:3865-74.
- Wong, W.T., Wang, M., Li, W. Regulation of Microglia by Ionotropic Glutamatergic and GABAergic Neurotransmission. Neuron Glia Biology, 2011;14:1-6.
- Zhao, L., Ma, W.X., Fariss, R.N., Wong, W.T. Minocycline attenuates photoreceptor degeneration in a mouse model of subretinal hemorrhage: microglial inhibition as a potential therapeutic strategy. American Journal of Pathology, 2011;179:1265-77. (Cover)
- Fontainhas, A.M., Wang, M, Liang, K.J., Chen, S., Mettu, P., Damani, M., Fariss, R.N., Li, W., Wong, W.T. Microglial Morphology and Dynamic Behavior is Regulated by Ionotropic Glutamatergic and GABAergic Neurotransmission. PLoS One, 2011;25;6(1):e15973.
- Damani, M., Zhao, L., Fontainhas, A.M., Amaral, J., Fariss, R.N., Wong, W.T. Age-related Alterations in the Dynamic Behavior of Microglia. Aging Cell, 2011;10:263-76.
- Wong, W.T., Kam, W., Cunningham D., Harrington, M., Hammel, K., Meyerle, C.B., Cukras, C., Chew, E.Y., Sadda, S.R., Ferris, F.L. Treatment of Geographic Atrophy by the Topical Administration of OT-551: Results of a Phase II Clinical Trial. Investigative Ophthalmology and Visual Science, 2010;51:6131-9.
- Ma, W., Zhao L., Fontainhas, A.M., Fariss, R.N., Wong, W.T. Microglia in the Mouse Retina Alter the Structure and Function of Retinal Pigmented Epithelial Cells: A Potential Cellular Interaction Relevant to AMD. PLoS One, 2009;4(11):e7945.doi:10.1371/journal.pone.0007945.
- Liang, K.J., Lee, J.E., Wang, Y.D., Fariss, R.N., Wong, W.T. Dynamic Behavior in Retinal Microglia is Regulated by CX3CR1 Signaling. Investigative Ophthalmology and Visual Science, 2009;50:4444-51.
- Zhao, L., Ma, W.X., Fariss, R.N., Wong, W.T. Retinal Vascular Repair and Neovascularization are not dependent on CX3CR1 Signaling in a Model of Ischemic Retinopathy. Exp Eye Res, 2009;88:1004-13.
Last Reviewed: April 2013