Retinal Pigment Epithelium (RPE).pptx retinal

Retinal pigment

1. Retinal Pigment Epithelium (RPE)

2. Retinal Pigment Epithelium (RPE) Structure and origins The retinal pigment epithelium 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

3. Relationship with neighboring tissues The RPE closely interacts with the underlying choriocapillaris and overlying photoreceptors Two specialized extracellular matrices on the RPE basal and apical surfaces enable this interaction 1 . 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 Rich in elastin and collagen, it provides only a minor contribution to the blood-retinal barrier

4. 2. Interphotoreceptor matrix This extracellular matrix is an interface between rod and cone outer segments (OS) and RPE cells It is found in the subretinal space, consisting of loosely organized proteins and proteoglycans * Lack of retinal pigment epithelial cell replication After birth, RPE cells lose the capacity for mitosis (cell division and replication)

5. Structure of the retinal pigment epithelial cell 2/23/2025 5

6. Functions of the retinal pigment epithelium Photoreceptor outer segment (OS) phagocytosis and renewal Light absorption and antioxidant protection Vitamin A metabolism and storage Barrier function (blood-retinal barrier) and control of fluid and ion transport between the retina and choriocapillaris Retinal adhesion Photoreceptor alignment Secretion of growth factors and immune modulators

7. Functions of the Retinal Pigment Epithelium RPE cells are highly metabolically active 1. Phagocytosis of photoreceptor outer segments (OS) Phagocytosis allows outer segment renewal Photoreceptor OS are exposed to a high volume of light-induced reactive oxidative agents 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

8. 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 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 ) 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- Drusens

9. Renewal and phagocytosis of photoreceptor outer segment discs 9

10. 2. Light absorption and anti-oxidative protections Light absorption leads to heat generation Melanin granules within RPE cells absorb scattered light to improve image quality This generates a large amount of heat, absorbed by the choriocapilaris To facilitate this heat sink, the choriocapillaris has a high blood flow, causing an oversupply of O2

11. Retinal pigment epithelial cell oxidative stress Excess light, heat, and O 2 expose RPE cells to oxidative damage 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

12. 3. Vitamin A metabolism and the visual cycle 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 It is taken up by the RPE from the underlying choroidal circulation

13. II. RPE storage and activation of vitamin A 99% of RPE vitamin A is stored in cytoplasmic droplets as retinyl ester, a stable, nontoxic form 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) 11-cis-retinal binds to cellular retinol-binding protein (CRALBP) within the RPE

14. III. Vitamin A transport to the photoreceptor OS 11-cis-retinal is shuttled across the subretinal space by interphotoreceptor matrix retinal binding protein (IRBP) The chromophore 11-cis-retinal forms a complex with a protein ( opsin ) to form visual pigment ( rhodopsin in rods) within OS discs

15. Vitamin A metabolism and the visual cycle 15

16. IV. Light reaction and subsequent events Light induces a conformational change of the chromophore from 11-cisretinal 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 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 intracellular droplets or used to regenerate 11-cis-retinal

17. Light adaptation Vitamin A metabolism is essential in regeneration of photopigments after strong light exposure 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

18. 4. Barrier function and fluid and solute transport I. Blood-retinal barrier maintenance 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) 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

19. II. Transepithelial transport Due to high paracellular resistance from intercellular tight junctions, molecules and ions flow across the RPE via transepithelial transport to: Supply nutrients to the photoreceptors Control ion homeostasis Eliminate excess water and metabolic waste products from retinal tissue 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 Active transcellular transport of biproducts of retinal metabolism (e.g., water and lactic acid) occurs from the subretinal space to the choriocapillaris

20. III. Metabolic pump Active transport is driven by apical Na+/K+ ATP ase pumps depleting intracellular Na+ The Na+ gradient is used to transport HCO3−, K + , Cl − , lactate, and H 2 O into cells from the subretinal space by means of Na+ /HCO 3 −, Na+ /K + / Cl−, and Na + /H 2 O/lactate cotransporters Excess intracellular Cl − exits across basal channels driving water towards the choroid 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

21. IV. Oxygen supply The choriocapillaris is the main source of oxygen for the outer retina Oxygen freely diffuses across Bruch’s membrane and the RPE to supply the outer retina

22. Retinal adhesion Possible mechanisms of retinal adhesion to the RPE include: Active flow of water from the subretinal space to choroid Interdigitation of RPE apical villous processes with photoreceptor outer segments Cohesive effect of the interphotoreceptor matrix

23. 6 . Photoreceptor alignment Interdigitation of photoreceptors with RPE apical processes may assist with maintaining photoreceptor alignment with the optical axis of the eye This maximizes light detection and discrimination (the Stile-Crawford effect) 7. Secretion The RPE secretes growth factors and immune modulators with various roles RPE secretion is regulated by paracrine and autocrine factors

24. Clinical Correlation Retinal Detachment Prolonged separation of the photoreceptors from the RPE can lead to permanent photoreceptor degeneration or reduced visual function due to altered photoreceptor alignment RPE in age-related macular degeneration (AMD) Genetic factors, age-related metabolic and phagocytic load, and cumulative oxidative and possibly inflammatory damage lead to accumulation of intracellular lipofuscin , lipid deposits in Bruch’s membrane, and RPE cell damage and death Choroidal neovascularization (CNV) Damage to Bruch’s membrane (e.g., AMD), new vessels from the underlying choroid can proliferate in either the sub-RPE or subretinal spaces forming a choroidal neovascular membrane (CNV)

25. Retinal Detachment * Symptoms Floaters : Small dark spots or squiggly lines that drift across vision   Flashing lights : A sudden appearance of light flashes in one or both eyes  Dark shadow : A shadow or "curtain" that appears in peripheral vision  Blurred vision : A gradual reduction in vision   Visual field defects : A gray curtain moving across field of vision 

26. There are three types of retinal detachment R hegmatogenous T ractional E xudative

27. Rhegmatogenous retinal detachement A tear or hole in the retina This allows fluid from within your eye to slip through the opening and get behind the retina . The fluid separates the retina from the retinal pigment epithelium This is the most common type of retinal detachment.

28. Tractional retinal detachment O ccurs when scar tissue on the retina’s surface contracts and causes the retina to pull away from the RPE. This is a less common type of detachment that typically affects people with  diabetes mellitus . Poorly controlled diabetes mellitus can lead to issues with the  retinal vascular system . This vascular damage can later lead to scar tissue accumulation that could cause retinal detachment.

29. E xudative detachment T here are no tears or breaks in the retina . Retinal diseases, such as the following, cause this type of detachment: - an inflammatory disorder causing fluid accumulation behind the retina - cancer behind the retina - Coats disease , which causes abnormal development in the blood vessels. The blood vessels leak proteins that build up behind the retina .

30. Case A 65 years old female patient came to OPD with a complain of sudden loss of vision. She reported that she experienced flashing of light before the visual loss. The examination reveals that she is a pathological myopic patient with -25.00 Ds of myopia. What do u expect from fundus examination? What type of fundus examination is best? What is her diagnosis?

31. Cont’d Vitamin A deficiency A common cause of eye disease, particularly in malnourished children or individuals with malabsorption . It can cause night blindness and changes in the fundus, cornea, or conjunctiva Stargardt’s disease Stargardt’s disease is a macular dystrophy due to a defective ABCR gene The defective gene results in accumulation of indigestible retinoid metabolites in the rod outer segment This leads to excess RPE lipofuscin accumulation and RPE toxicity RPE65 mutations- Mutations in RPE65 The Arden ratio- The ratio of the light rise to the dark dip on the EOG

32. Neurophysiology of the Eye

33. Optic Nerve The optic nerve is a central nervous system (CNS) white matter tract that transmits visual information from the eye to the brain The optic nerve consists of: (a) Retinal ganglion cell (RGC) axons (b) Supportive glial tissue (c) Vascular tissue Surrounded by three layers of meningeal tissue ( pia , arachnoid, and dura )

34. The RGC axons Course along the retinal nerve fiber layer (RNFL) to enter the optic disc Continue through the intraorbital , intracanalicular , and intracranial portions of the optic nerve Pass through the optic chiasm and optic tract toward the CNS The optic nerve has a limited capacity for regeneration after significant damage, resulting in irreversible visual loss

35. Optic Nerve Parenchyma: Cellular Components Glial cells provide structural and metabolic support for the RGC axons. 1. Oligodendrocytes Oligodendrocytes form a myelin sheath around axons posterior to the lamina cribrosa Myelin, a fatty multilaminated structure, provides electrochemical insulation to the axon Each oligodendrocyte has 20–30 processes that each myelinate a small portion of an axon Between each segment of myelin is the node of Ranvier The action potential jumps from one node to the other ( saltatory conduction) to greatly increase the speed and efficiency of conduction

36. Oligodendrocyte origins and development Oligodendrocytes are derived from oligodendrocyte precursor cells that migrate from the brain Their differentiation and renewal is controlled by neurotrophic factors including: (a) Platelet-derived growth factor (PDGF) (b) Basic fibroblast growth factor (b FGF) Myelination begins at 32 weeks gestation from the lateral geniculate nucleus Myelination progresses as far as the lamina cribrosa ; the process is complete by 2 years of age Oligodendrocytes and ganglion cell axons interact to influence their growth and metabolic functions during development and throughout adulthood

37. Astrocytes Astrocytes are common CNS glial cells that express glial fibrillary acid protein They provide crucial supportive functions within the optic nerve, including: I. Maintenance of water and electrolyte (especially K + ) homeostasis Electrolyte homeostasis is necessary for optimal electrical function of the axon K + is released by axons on action potential repolarization Astrocytes absorb excess extracellular K +

38. Cont’d II. Metabolic supply to axons Astrocytes store glycogen They can shuttle lactate to adjacent axons in ischemic or hypoglycemic states III. Maintenance of neural tissue barriers Astrocytic foot processes maintain the blood–brain barrier at capillary basement membrane and pial surfaces They regulate levels of extracellular neurotransmitters and solutes at the nodes of Ranvier

39. IV. Response to optic nerve injury Astrocytes hypertrophy and extend cellular processes in response to parenchymal injury or loss, a process known as gliosis * Optic nerve glioma V. Axonal growth and development Astrocytes act as a scaffold for axon growth in the developing optic nerve In the mature optic nerve, astrocytes inhibit axonal regrowth

40. Microglia These are bone marrow-derived phagocytic scavenger cells that resemble Macrophages They move to sites of injury, proliferate, phagocytose , and degrade extracellular Material They express cell surface antigen, stimulating T-lymphocytes and activating the immune system

41. Clinical correlation Optic neuropathy Glaucoma Compressive optic neuropathy Demyelinating disease Papilledema Ischemic optic neuropathy Optic nerve astrocytoma