I specialize in vitreoretinal surgery and have dedicated my career to elucidating the pathogenesis of vitreoretinal diseases. Although advances in vitreous surgery have dramatically improved treatment outcomes for various vitreoretinal diseases, fundamental questions still arise in daily surgical practice. In this article, I will focus on elucidating the following five items among our previous studies that began with simple questions arising in clinical practice.
I. Retinogenesis in the fovea
Despite persistent photostress, the fovea maintains its morphology and functions without cell depletion throughout life. Moreover, macular holes in the fovea, unlike those in other parts of the retina, regenerate and regain their original morphology without scarring after closure. This phenomenon is similar to scarless fetal-skin wound healing. Based on our hypothesis that retinal stem cell-like undifferentiated cells exist in the fovea and are involved in tissue homeostasis, regeneration, and repair, we performed immunohistological studies using monkey retinas. Our results indicated that several kinds of undifferentiated cells, including the red and green cones in the foveola, generate neurons and glia that supply the surrounding retina and may contribute to the maintenance of morphology and regeneration of the foveola.
II. The bursa premacularis (BPM) and macular diseases
The BPM is a peculiar sac-like structure located in the vitreous body in contact with the macula; its physiological roles remain unknown. We histologically examined the BPM specimens collected during vitrectomy and found that the BPM contained mast cells, which produce physiologically active substances such as chymase and tryptase, suggesting the involvement in the pathogenesis of macular holes and epimacular membranes. In addition, lymphatic vessel markers, such as lymphatic vessel endothelial hyaluronan receptor (LYVE) -1 and podoplanin, were expressed in the BPM, suggesting that the BPM plays the role of the lymphoid tissue for the excretion of water and waste products to maintain macular function.
III. In the most peripheral regions of the retina and retinogenesis around the optic disc
The red and green cones in the foveola, considered to have retinal stem cell-like functions, lose their outer segments in various diseases, whereas the foveal cones lack outer segments in the fetal period. Immunohistological studies on monkey retinas showed that undifferentiated cones devoid of outer segments existed around the optic disc and in the transitional zone between the retina and the ciliary body. On the basis of our hypothesis that undifferentiated cells, including red and green cones, generate the neurons and astrocytes that supply the surrounding retina, I investigated the pathogenesis of macular diseases, glaucoma, and peripheral retinal degeneration.
IV. Causes of retinal lattice degeneration
We immunohistologically examined the retinal lattice degeneration specimens collected during vitrectomy and found that RPE65 and pan-cytokeratin (CK), retinal pigment epithelial (RPE) cell markers, were expressed in the degenerated area. This result suggests that during the eyeball growth phase, the generation of neurons by retinal stem cell-like cells supplying the most peripheral regions of the retina cannot keep up with the scleral extension speed, and RPE cells dedifferentiate for compensation, migrate, proliferate, and degenerate in the retina, causing retinal lattice degeneration.
V. Causes of cystoid degeneration of the peripheral retina
We histologically examined cystoid degeneration of the peripheral retina in young dogs, and found two types of cysts, large and small cysts. Large cysts contained numerous apoptotic cells, whereas small cysts expressed blastocyst markers formed in the early stages of embryogenesis before implantation and were morphologically very similar to blastocysts. Cdx2 and CK18 were expressed in the cyst wall, and Oct4, and Sox2 were expressed in the inner cell mass. RPE65 positive cells were observed around the cysts, suggesting that the blastocyst-like structures were formed by the migration and differentiation of RPE cells. The large cysts may develop due to impaired differentiation of the blastocyst-like small cysts.
Nippon Ganka Gakkai Zasshi (J Jpn Ophthalmol Soc) 126: 254-297,2022.