Interactions between neural retina, retinal epithelium and choroid

The retinal pigment epithelium (RPE) is a non-replicating monolayer that plays a key role nursing the photoreceptors of the neural retina, regulating fluid movement within the subretinal space, maintaining a basal laminar layer of Bruch s membrane, and influencing the choriocapillaris. This project investigates how surgical manipulation of the retinal epithelial layer influences the neural retina, the choroid and the epithelial layer itself.

Bleb detachment is a surgical method to gain access to the subretinal space by separating the neural retina from the RPE, which can be therapeutically useful in procedures such as gene therapy and retinal cell transplantation. This method of separating the RPE from the photoreceptors is not without complications because it can produce a number of abnormalities in the RPE itself as well as in the neural retina and choroid. Jet stream pressure, the standard way to produce a bleb detachment, causes focal damage to the RPE layer and choroid and generalized damage to the apical membranes of the RPE. It also produces folds in the rabbit neural retina, which induce a gradual transformation of the RPE layer. This transformation leads to migration, proliferation and a defect in lysosomal digestion that has been associated with apoptosis. Such changes produced by bleb detachment may explain the gradual loss of RPE allografts or homografts.

Photoreceptor transplants survive for a long period of time and can develop outer segments without showing evidence of apoptosis. But such photoreceptor transplants form abnormal rosettes, which may also be due to abnormalities produced in the RPE layer by bleb detachments. These problems associated with the production of bleb detachments should be considered in any attempts to introduce solutions and/or cells into the subretinal space.

Attempts to reconstruct or repair the RPE layer by transplantation can involve the removal of RPE cells from Bruch s membrane before replacing them with transplanted cells; it can also involve biopsy of RPE cells for culture or transplantation to another site. The removal of RPE cells from Bruch s membrane causes significant changes in the choroid. Removal of large areas of RPE leads to inflammation and fibrosis in the choroid that compresses the large choroidal vessels leading to reduction of blood flow in the terminal choriocapillary beds. The absence of an RPE layer without its replacement may also cause atrophy of the choriocapillaris by the loss of a hypothetical trophic factor. Even slight pressure on the RPE layer without any removal of cells leads to rapid but reversible reduction in flow of large choroidal vessels, which appears to be due to vasospastic constriction and/or thrombosis. Because the recovery from such changes can take hours or days, this abnormality could lead to degeneration of the neural retina and may be related to other choroidal abnormalities.

Removal of local segments of the neural retina causes profound changes in the adjacent RPE layer, which are even more pronounced than what is observed in bleb detachments or what has been described after prolonged retinal detachments. It reveals that the neural retina must inhibit the transformation of the RPE layer by releasing a factor that suppresses this response.

The results are important for understanding how to enter and manipulate the structures bordering the subretinal space, the photoreceptors, the retinal epithelium and the choroid. It offers insights into how the methodology for surgical repair of these structures such as gene therapy and/or transplantation can be made more effective.

List of scientific papers

I. Ivert L, Gouras P, Naeser P, Narfstrom K (1998). Photoreceptor allografts in a feline model of retinal degeneration. Graefes Arch Clin Exp Ophthalmol. 236(11): 844-52.
https://pubmed.ncbi.nlm.nih.gov/9825260

II. Ivert L, Kjeldbye H, Gouras P (2002). Long-term effects of short-term retinal bleb detachments in rabbits. Graefes Arch Clin Exp Ophthalmol. 240(3): 232-7. Epub 2002 Feb 15
https://pubmed.ncbi.nlm.nih.gov/11935282

III. Ivert L, Kong J, Gouras P (2003). Changes in the choroidal circulation of rabbit following RPE removal. Graefes Arch Clin Exp Ophthalmol. 241(8): 656-66.
https://pubmed.ncbi.nlm.nih.gov/12883908

IV. Ivert L, Kong J, Gouras P (2006). Alteration in choroidal blood flow produced by local pressure. Graefes Arch Clin Exp Ophthalmol. Mar 17: 1-6.
https://pubmed.ncbi.nlm.nih.gov/16544112

V. Ivert L, Gouras P (2006). Behavior of retinal epithelium to bleb detachment versus retinectomy. Graefes Arch Clin Exp Ophthalmol. Apr 25: 1-6.
https://pubmed.ncbi.nlm.nih.gov/16636838

VI. Ivert L, Keldbye H, Gouras P (2005). Age-related changes in the basement membrane of the retinal pigment epithelium of Rpe65 -/- and wild-type mice. Graefes Arch Clin Exp Ophthalmol. 243(3): 250-6. Epub 2004 Sep 17
https://pubmed.ncbi.nlm.nih.gov/15378383