The Retinal Pigment Epithelium




(1)
University of Sydney, Sydney, Australia

 




Overview




1.

Structure and origins



  • The retinal pigment epithelium (RPE) is a hexagonally packed, monolayer of cuboidal epithelial cells that separates the neural retina from the choroid.


  • Embryologically, it is derived from the outer wall of the optic cup [1].

 

2.

Relationship with neighboring tissues (Fig. 9.1)

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Fig. 9.1
Structure of the retinal pigment epithelial cell




  • The RPE closely interacts with the underlying choriocapillaris and overlying photoreceptors [2].


  • Two specialized extracellular matrices on the RPE basal and apical surfaces enable this interaction:


(i)

Bruch’s membrane



  • This 5-layered membrane is a molecular sieve that partly regulates the reciprocal exchange of oxygen, fluids, nutrients, and waste products between the retina and choriocapillaris [3].


  • Rich in elastin and collagen, it provides only a minor contribution to the blood-retinal barrier.

 

(ii)

Interphotoreceptor matrix



  • This extracellular matrix is an interface between rod and cone outer segments (OS) and RPE cells [4].


  • It is found in the subretinal space, consisting of loosely organized proteins and proteoglycans.

 

 

3.

Functions of the retinal pigment epithelium (Table 9.1)


Table 9.1
Functions of the retinal pigment epithelium [2, 5, 6]






























 
Function

1
Photoreceptor outer segment (OS) phagocytosis and renewal

2
Light absorption and antioxidant protection

3
Vitamin A metabolism and storage

4
Barrier function (blood-retinal barrier) and control of fluid and ion transport between the retina and choriocapillaris

5
Retinal adhesion

6
Photoreceptor alignment

7
Secretion of growth factors and immune modulators

 

4.

Lack of retinal pigment epithelial cell replication



  • After birth, RPE cells lose the capacity for mitosis (cell division and replication) [7, 8].

 


Structure of the Retinal Pigment Epithelium




1.

Gross structure



  • The RPE extends to the ora serrata where it is continuous with the ciliary pigment epithilium.


  • It ends posteriorly at the border of the optic disc.

 

2.

Cellular organization [8, 9]



  • The RPE contains approximately 3.5 million cells arranged in a regular hexagonal pattern.


  • At the posterior pole, the cells are tall slender, and densely packed.


  • Towards the periphery, the cells are flatter, wide, and pleomorphic.


  • On average, there are 23 photoreceptors per RPE cell [10].

 

3.

Cell architecture (Fig. 9.1)



  • RPE cells are polarized with distinctive apical and basal membranes [11].


  • Microvilli arise from the apical membrane and envelope the photoreceptor outer segments [12].


  • Anterolaterally, the cells are joined by junctional complexes that contain numerous tight junctions.


  • This forms an effective barrier for fluid and solutes between the choroid and subretinal spaces [13].


  • Beneath the junctional complexes, numerous gap junctions link the cells electrically [14].


  • RPE cells contain numerous apical pigmentary melanin granules that absorb light [14].


  • Lipofuscin granules, containing residue of digested photoreceptor material, are found basally in the RPE cells. They are more numerous towards the posterior pole and fovea [15].

 


Functions of the Retinal Pigment Epithelium


RPE cells are highly metabolically active.

1.

Phagocytosis of photoreceptor outer segments (OS) (Fig. 9.2)

A347009_1_En_9_Fig2_HTML.gif


Fig. 9.2
Renewal and phagocytosis of photoreceptor outer segment discs (based on Kolb) [21]


(i)

Phagocytosis allows outer segment renewal.



  • Photoreceptor OS are exposed to a high volume of light-induced reactive oxidative agents [16].


  • To prevent accumulative oxidative damage, OS undergo continuous renewal: new membrane is added at the inner segment junction and old material removed from the tip by RPE phagocytosis [17].

 

(ii)

Regulation of phagocytosis.



  • Outer disc shedding follows circadian regulation and is maximal after morning light onset.


  • It takes approximately 11 days to renew the whole length of the OS [18].


  • OS binding is coordinated by the RPE apical receptor α v β 5 -integrin, OS internalization by CD36, and activation of phagocytosis by receptor tyrosinekinase c-mer (MerTK) [19].

 

(iii)

RPE phagocytic load.



  • RPE cells have a high phagocytic load, ingesting and degrading much OS material through life.


  • This phagocytic and metabolic load causes RPE lipofuscin accumulation with age [20].

 

 

2.

Light absorption and anti-oxidative protections

(i)

Light absorption leads to heat generation.



  • Melanin granules within RPE cells absorb scattered light to improve image quality [14].


  • This generates a large amount of heat, absorbed by the choriocapilaris [22].


  • To facilitate this heat sink, the choriocapillaris has a high blood flow, causing an oversupply of O2.

 

(ii)

Retinal pigment epithelial cell oxidative stress



  • Excess light, heat, and O2 expose RPE cells to oxidative damage [8].


  • High metabolic activity and age-related lipofuscin accumulation exacerbate oxidative stress.


  • RPE cells are protected from oxidative damage by plentiful antioxidants including ascorbate, glutathione, and carotenoids lutein, zeaxanthin, and β-carotene, as well as melanin pigments [23, 24].

 

 

3.

Vitamin A metabolism and the visual cycle (Fig. 9.3)

A347009_1_En_9_Fig3_HTML.gif


Fig. 9.3
The visual cycle [30]




  • RPE is involved in the storage and metabolism of vitamin A (retinol) and its derivatives (retinoids).


(i)

RPE uptake of circulating vitamin A



  • Free vitamin A is insoluble in serum and toxic to cell membranes.


  • It travels in the blood as all-trans-retinol bound to retinol-binding protein/transthyretin complex [25].


  • It is taken up by the RPE from the underlying choroidal circulation [5].

 

(ii)

RPE storage and activation of vitamin A



  • 99% of RPE vitamin A is stored in cytplasmic droplets as retinyl ester, a stable, nontoxic form [26].


  • This can be converted to 11-cis-retinal, the key chromophore of the visual pigments.


  • This conversion occurs via a complex involving RPE65, which acts as an isomerase, and lecithin:retinol transferase (LRAT) [27, 28].


  • 11-cis-retinal binds to cellular retinol-binding protein (CRALBP) within the RPE.

 

(iii)

Vitamin A transport to the photoreceptor OS



  • 11-cis-retinal is shuttled across the subretinal space by interphotoreceptor matrix retinal binding protein (IRBP) [ 29].


  • The chromophore 11-cis-retinal forms a complex with a protein (opsin) to form visual pigment (rhodopsin in rods) within OS discs.

 

(iv)

Light reaction and subsequent events



  • Light induces a conformational change of the chromophore from 11-cis-retinal to all-trans-retinal.


  • All-trans-retinal leaves the disc membrane via ATP-binding cassette protein transporter ABCR4.


  • It is converted into all-trans-retinol and transported back to the RPE via IRBP [31].


  • Within the RPE cell, it binds to cellular retinol-binding protein (CRBP) and interacts with the RPE65/LRAT complex.


  • Depending on differential RPE65 function in light and dark, the retinol is either esterified for storage in intracelular droplets or used to regenerate 11-cis-retinal [28, 32].

 

(v)

Light adaptation (See Chap. 21. Luminance Range for Vision)



  • Vitamin A metabolism is essential in regeneration of photopigments after strong light esposure [33].


  • In light, there is a rapid turnover of retinal; in the dark, turnover occurs more slowly.


  • Rapid bleaching of pigment in light and slower photopigment regeneration in dark are important components of visual adaptation to different light intensities.


  • Pigment regeneration involves sequential recruitment of vitamin A sources IRPB, CRALBP, and RPE65 [34].

 

 

4.

Barrier function and fluid and solute transport (Fig. 9.4)

A347009_1_En_9_Fig4_HTML.gif


Fig. 9.4
Solute and fluid movement across RPE cells


(i)

Blood-retinal barrier maintenance (See Chap. 11. Ocular Circulation)



  • The tight junctional complexes around the RPE cells maintain the blood-retinal barrier (the barrier between blood from the choroid and OS of the photoreceptors) [35].


  • This regulates solute flow to the retina, maintaining tight control of extracellular composition.


  • The blood-retinal barrier also maintains the immune privilege of the eye [36].

 

(ii)

Transepithelial transport



  • Due to high paracellular resistance due to intercellular tight junctions, molecules and ions flow across the RPE via transepithelial transport to:


a.

Supply nutrients to the photoreceptors

 

b.

Control ion homeostasis

 

c.

Eliminate excess water and metabolic waste products from retinal tissue [35, 37]

 




  • Energy-dependent transport of glucose, all-trans-retinol and docosahexaenoic acid (an ω-3 fatty acid needed for OS renewal) occurs from the choriocapillaris to the interphotoreceptor matrix [38, 39].


  • Active transcellular transport of biproducts of retinal metabolism (e.g., water and lactic acid) occurs from the subretinal space to the choriocapillaris [39, 40].

 

(iii)

Metabolic pump

(a)

Active transport is driven by apical Na+/K+ ATPase pumps depleting intracellular Na+ [37].

 

(b)

The Na+ gradient is used to transport HCO3 −, K+, Cl−, lactate, and H2O into cells from the subretinal space by means of Na+/HCO3 −, Na+/K+/Cl−, and Na+/H2O/lactate cotransporters [41, 42].

 

(c)

Excess intracellular Cl− exits across basal channels driving water towards the choroid [43].

 

(d)

This energy-dependent transfer of solutes and water provides the RPE with a capacity for pumping out excess fluid despite high oncotic pressure of the interphotoreceptor matrix [44].

 

 

(iv)

Oxygen supply



  • The choriocapillaris is the main source of oxygen for the outer retina [45].


  • Oxygen freely diffuses across Bruch’s membrane and the RPE to supply the outer retina.

 

 

5.

Retinal adhesion

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Oct 28, 2016 | Posted by in OPHTHALMOLOGY | Comments Off on The Retinal Pigment Epithelium

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