Review Article

The Mammalian Ocular Lens in Focus: Development, Anatomy, Physiology, Transparency, Biomechanics, and Age-related Challenges

DOI:

10.3791/70442

⸱

May 29th, 2026

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1School of Optometry and Vision Science Program, Indiana University

In This Article

Summary

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The function of the ocular lens to focus light onto the retina depends on tissue transparency, biomechanics, and refractive index. This review highlights the three-dimensional architecture of the lens and discusses the complex mechanisms that maintain tissue homeostasis.

Abstract

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The lens is a transparent, ellipsoid organ in the anterior chamber of the eye that focuses light onto the retina. Composed of epithelial cells and fiber cells, this 3-dimensional tissue is highly organized to ensure a clear light path and utilizes multiple strategies to establish and maintain a high refractive index and transparency. In humans, the lens undergoes shape changes to focus light from different distances in a process known as accommodation, and these elastic and biomechanical properties of the lens rely on tissue, cellular, and molecular mechanisms. Cataracts, defined as any opacity in the normally transparent lens, remain the leading cause of blindness in the world. Presbyopia, due to age-related changes in lens stiffness, has been linked to accommodative decline and the need for reading glasses. This review will explore mammalian lens development and lifelong growth, crystallins and cytoskeletal proteins, cell-cell communication and microcirculation, lens biomechanics, and the challenges and novel methods for studying this unique tissue.

Introduction

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The ocular lens is, at first glance, a relatively simple tissue composed of two cell types, epithelial cells and fiber cells. The bulk mass of the lens is made up of fiber cells, and there is a monolayer of epithelial cells covering the anterior hemisphere1 (Figure 1A). The entire tissue is encased in a thin basement membrane, called the lens capsule, that is primarily made of collagen IV and laminin, as described in a previous review2. Lacking a blood supply and nerves, the lens is suspended in the anterior chamber of the eye by elastic zonular fibers (aka zonules) connecting the lens capsule to the ciliary body1. Anterior or central lens epithelial cells are cuboidal and arranged in a cobblestone pattern3,4,5 (Figure 1A, light blue cells, top). These cells are quiescent and do not proliferate6. Just anterior of the lens equator, epithelial cells divide in the germinative zone (Figure 1A, orange cells, top right), and these equatorial cells will migrate toward the equator where they become highly ordered into meridional rows with hexagonal cell shape7,8,9,10 (Figure 1A, green cells, top right). Meridional row cells anchor their apical tips at the lens fulcrum or modiolus and begin to elongate and differentiate into new secondary fiber cells (Figure 1A, lower left). Apical tips of secondary fibers migrate toward the anterior pole by interacting with the apical side of epithelial cells, forming an unusual apical-apical junction3 (Figure 1A, red line). The posterior basal tips of newly formed fibers extend toward the posterior pole by moving along the lens capsule (Figure 1A, lower left). Once the tips of elongating fiber cells reach the anterior or posterior pole, the cells detach from the anterior epithelial cells or posterior capsule and meet the tips of cells extending from the opposite side of the tissue to form the suture11,12,13 (Figure 1A, top left). Lens fiber cells are an elongated hexagonal shape in cross section with 2 long/broad sides, 4 short sides, and 6 tricellular junctions (Figure 1A, bottom right)14. Minimal intercellular space between neighboring fiber cells reduces light scattering14. The continuous addition of cortical fiber cells at the periphery, overlaid onto previous generations of fibers, facilitates lifelong growth of the lens14,15. The center of the lens is called the nucleus, and this region of the lens has increased stiffness compared to the periphery or cortex, as described in a previous review16.

Lens anatomy diagram illustrating fiber organization, cell types, and SEM micrographs of cortical fibers.
Figure 1: Lens anatomy and structure. (A) The lens is composed of a monolayer of epithelial cells (light blue, orange, and light green) covering the anterior hemisphere and a bulk mass of lens fibers (white and pink). A thin collagenous membrane, known as the lens capsule (tan), encapsulates the tissue. The lens is suspended in the anterior chamber of the eye by zonular fibers (zonules) inserted in the capsule around the lens equator. Anterior/central epithelial cells (light blue, top) are cuboidal in shape and cobblestone in cross-section. Equatorial epithelial cells (orange) in the germinative zone transform from randomly packed cells (orange) into organized meridional rows of hexagonal cells (green). Meridional row cells elongate to become new layers of cortical secondary fiber cells (white) at the lens periphery. The apical tips of newly formed secondary fibers anchor at the fulcrum/modiolus (periwinkle box, lower left). The apical tips of elongating secondary fibers migrate toward the anterior pole along the apical side of lens epithelial cells and form an unusual apical-apical junction (red line). The basal tips of elongating fibers migrate toward the posterior pole along the posterior capsule. When secondary fibers are fully elongated, the tips detach from the anterior epithelium or posterior capsule to form the lens suture (dark blue lines and top left image). Lens fiber cells are elongated hexagons in cross section (lower right) with 2 long/broad sides, 4 short sides, and 6 tricellular junctions. During fiber cell maturation, all cellular organelles are removed to form the organelle-free zone (dark green double-headed arrow) and minimize light scattering. The oldest lens fiber cells are compacted into the center of the tissue to form the lens nucleus (pink). Cartoons are not drawn to scale. (B) Scanning electron microscope images of fiber cells at different depths in the lens show the changing cell morphology during differentiation and maturation. Single cells are highlighted in green for emphasis. Cortical peripheral fibers have ball-and-socket interdigitations along the long sides and small protrusions along the short sides. During fiber cell maturation, large paddles decorated with small protrusions and large protrusions decorate the short sides of the mature cells. Perinuclear fibers have tongue and groove interdigitations along the entire membrane and large protrusions along the short sides. Nuclear fibers have large protrusions along the short sides and globular membrane morphology. Scale bar, 5 µm. Modified from 16,328. Please click here to view a larger version of this figure.

The complexity of the lens lies in the highly ordered three-dimensional (3D) cell arrangement, specialized fiber cell maturation that degrades and removes all cellular organelles, and molecular and cellular mechanisms to establish and maintain transparency and high refractive index of the tissue. The lack of cellular organelles in most lens fiber cells increases the difficulties in maintaining the health and longevity of every lens cell ever made throughout an organism’s lifetime. The lens is an excellent tissue for studying aging and age-related changes because the centermost cells were made during early embryonic development, and the lens continues to generate new cells at the periphery of the tissue throughout life, allowing the study of cells that are chronologically old vs. cells made during old age. The fine focusing function of the lens allows a clear image to be formed on the retina from objects at different distances and depends on the ability of the lens to change shape or accommodate. The lens is a non-connective and non-muscle tissue where biomechanical properties are required for normal function.

The leading cause of visual impairment is aging17. Age-related changes lead to two major lens pathologies, cataracts and presbyopia18. Cataracts or any lens opacity remain the leading cause of blindness in the world19 and are caused by genetic and environmental factors, including UV radiation, smoking, diabetes, and oxidative stress, that lead to protein aggregation and/or cell defects, as described in previous reviews18,20,21,22,23,24,25. Presbyopia, an age-related decrease in accommodation, is caused by a reduction in the lens’s ability to change shape when focusing on near objects , and, by extension, the need for reading glasses26,27,28. The World Health Organization estimates that there are at least 1 billion people globally with unaddressed visual impairment, including 65.2 million people with cataracts and 826 million people with presbyopia17. With an aging population, there is an urgent need to better understand the physiology and biology of the lens.

This review covers tissue architecture, cell arrangement, and molecular mechanisms that are important for the function and homeostasis of mammalian lenses, with some info on lenses from other vertebrates. The goal is to give a general overview of lens biology and physiology with references to additional detailed reviews. Topics include embryonic lens development, postnatal lens growth, 3D cell and tissue arrangement, the biomechanical properties of the tissue, and microcirculation. Major lens proteins, namely the crystallins, cytoskeletal networks, and cell-cell communication, are discussed below. The review will conclude with current challenges and novel methods for studying this unique tissue.

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Review and Perspective

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Embryonic Lens Development and Postnatal Lens Growth

In vertebrates, the lens develops from surface ectoderm cells, and the future lens begins with thickening of the surface ectoderm above the optic vesicle6,29,30 (Figure 2A). In conjunction with the formation of the optic cup, the thickened ectoderm or lens placode invaginates into the lens pit6,29,30 (Figure 2B). Actin filaments (F-actin) attach the posterior lens pit to the anterior surface of the developing optic cup to coordinate the movement and shape changes of these developing tissues31,32,33,34, and apical constriction of lens epithelial cells is required for lens pit invagination35,36,37,38,39,40 (Figure 2C). The opening of the lens pit continues to narrow until the hole is closed, as lens stalk cells undergo apoptosis41,42,43. The lens vesicle is separated from the future corneal ectoderm to form the lens vesicle, a hollow sphere of epithelial cells6,29,30 (Figure 2D). Posterior epithelial cells in the lens vesicle elongate toward the anterior epithelium and differentiate into primary fiber cells to fill the cavity and form the embryonic lens (Figure 2E). The monolayer of epithelial cells covering the anterior hemisphere is maintained while there are no posterior epithelial cells in the fully formed embryonic lens (Figure 2F). Primary fiber cells form the centermost portion of the lens nucleus and are surrounded by new generations of secondary lens fibers that are added from the lens periphery or cortex throughout life6,29,30. While most vertebrate lenses form by invagination, in zebrafish, the placode thickens and then delaminates to form the lens44.

Lens development stages; diagrams show optic vesicle to embryonic lens formation steps.
Figure 2: Embryonic lens development in mammalian eyes. Surface ectoderm cells are white, lens cells are light blue, and optic cup/vesicle cells are sand color. (A) The embryonic lens placode (light blue) develops from the surface ectoderm. Posterior to the surface ectoderm and lens placode is the optic vesicle. (B) Invagination of the lens placode forms the lens pit, and the invagination of the optic vesicle forms the optic cup. The anterior optic cup will develop into the iris and ciliary body, while the posterior optic cup will form the retina and retinal pigmented epithelium. (C) The lens placode opening narrows until the opening is closed. (D) The lens vesicle separates from the surface ectoderm and is a hollow sphere lined with lens epithelial cells. (E) Posterior lens epithelial cells in the lens vesicle will start to elongate and differentiate into primary lens fibers. (F) Primary lens fibers fill the cavity of the lens vesicle to form the embryonic lens. Cartoons are not drawn to scale. Modeled after 411. Please click here to view a larger version of this figure.

During embryonic development, the lens is surrounded by a basket-like network of blood vessels6,45,46. These vessels originate from the hyaloid artery of the retina and begin to form a network at the posterior of the lens pit and eventually create an ordered meshwork of the tunica vasculosa lentis to nourish the embryonic lens until the anterior chamber and aqueous humor production are fully developed6,45. These vessels regress and disappear to ensure a clear light path before birth or before eye opening, depending on the species6,45,46,47.

Pax6 is necessary for early eye development48,49,50,51,52 and is essential and sufficient for lens development53,54,55,56. Phosphorylation and SUMOylation of Pax6 regulate the function of this transcription factor during brain, central nervous system, and eye development57,58,59,60. Other important signaling pathways that are required for embryonic eye and lens development intersect with Pax6 signaling, including enhancers [Meis, bone morphogenic proteins (Bmp), and fibroblast growth factor (FGF)] and downstream proteins [Foxe3 and retinoic acid (RA)], as described in a previous review61. Meis1 and Meis2 bind to the enhancer region of the Pax6 gene and are required for lens induction in vertebrates62. Genetic studies show that Bmp7 is required for the development of the lens placode by regulating Pax6 expression63,64. Foxe3 is downstream of Pax6 signaling and is needed for lens development65,66, particularly the clean separation of the lens stalk from the surface ectoderm when the lens vesicle is formed. Loss of Foxe3 leads to congenital eye defects known as Peters Anomaly67. FGF receptor (FGFR) signaling cooperates with Bmp7 to regulate Pax6 expression, which in turn affects Foxe3 levels in the developing lens68. Expression of an inhibitory form of FGFR leads to a delay in lens placode formation, incomplete separation of the lens stalk, and a small lens vesicle68. Disruption of RA signaling leads to eye formation defects69, and when Pax6 is disrupted, there is decreased expression of RA, suggesting some crosstalk between the two signaling pathways70.

After the embryonic lens is fully formed, continuous lens growth through the proliferation and differentiation of equatorial epithelial cells into secondary lens fibers is thought to be driven by growth factor signaling, primarily through FGF in mammalian lenses, as described in a previous review71. FGFs are more abundant in the vitreous than the aqueous humor, setting up a gradient of increasing growth and differentiation signals near the lens equator72,73. The lens expresses 3 of 4 FGFRs, FGFR1, FGFR2, and FGFR3, with increasing expression at and posterior to the lens equator74,75. Overexpression of FGFs induces abnormal elongation and differentiation of normally quiescent anterior epithelial cells into fiber-like cells76,77,78. In addition to FGF signaling, inhibitor assays indicated that the Bmp pathway plays a role in fiber cell elongation79,80, and an abnormal transforming growth factor beta (TGFβ) receptor disrupts normal fiber cell maturation81.

Lens Transparency and Refractive Index

Lens fiber cells undergo a specialized process to remove all cellular organelles during maturation to eliminate light-scattering objects in the light path and to create the organelle-free zone (OFZ)82 (Figure 1A). The coordinated loss of all cellular organelles occurs rapidly once fiber cells reach a specific stage of their maturation programming83,84,85,86,87,88. Abnormal organelle degradation leads to cataracts, and several knockout (KO) zebrafish and mouse models have identified genes for chromatin and DNA degradation89,90,91,92,93, cyclin-dependent kinases94,95, heat shock factor 491,96,97,98, and PLATT phospholipase99 that are important for the formation of the OFZ. Abnormal expression or mutations in cell membrane and cytoskeletal proteins100,101,102,103,104, crystallins105,106,107, and oncogenes108,109 can also affect organelle removal and lens transparency. However, the exact signal that triggers organelle degradation in fiber cells remains unclear. Recent work has revealed the importance of RNA-binding proteins in lens development and cataractogenesis, as described in a previous review110. Disruption of RNA-binding proteins, including Tdrd7111, caprin2112, Rbm24113, and Celf1114,115,116 lead to abnormal lens development, disrupted organelle degradation, and cataracts.

Compared to most cell types in the body, mammalian lens fiber cells have extremely high protein concentration (200–450 mg/ml)117,118,119,120. Proteins make up 30%–35% of total lens weight, and consequently, the lens has relatively low water content, about 65%–70%121,122. Ninety percent of lens proteins by mass are crystallins123, and there are 3 families of crystallin proteins in mammalian lenses, α, β, and γ, as described in previous reviews124,125. High protein content would normally increase the risk of aggregates that are larger than half the wavelength of light, leading to light scattering126, but crystallin proteins are organized in the fiber cell cytoplasm with short-range order to promote high refractive index and transparency117,127. Protein aggregation is attenuated by the chaperone-like functions of α-crystallins, discussed below. The gradient refractive index (GRIN) across the lens promotes light focusing, as described in previous reviews128,129, and the maximum refractive index at the center of the lens is correlated with the compaction of nuclear fiber cells130,131,132. In fish lenses, data suggest that a high refractive index in the nucleus is a result of protein transport into the center of the tissue133. The uniform distribution of crystallin proteins across cells and between shells of fibers is hypothesized to be facilitated by a macromolecular transport pathway through membrane fusions along fiber cell membranes134,135. However, membrane fusions have not been clearly observed in mouse lenses136,137,138, and impedance studies in lenses from multiple species do not detect membrane fusions139,140,141,142. Data from mouse models with disruption of gap junction communication suggest that cell-to-cell communication and fiber cell elongation also contribute to the macromolecular transport pathway143.

Crystallins are ~20–30 kDa in molecular weight and play a structural and refractive role in the lens. Alpha-crystallins are made up of αA and αB subunits, which share 55%–60% homology144,145,146, and while αB is ubiquitously expressed in most cells, αA-crystallin is predominantly expressed in the lens and has been detected at low levels in other tissues, including the spleen and thymus147,148. Recent work has also shown that retinal pigmented epithelial cells and retinal ganglion cells can express αA-crystallin during stress or disease, presumably to provide a neuroprotective effect149,150,151. Alpha-crystallins typically associate into large heteromultimers of 30–35 mixed αA and αB subunits123. In the mouse, bovine, and human lens epithelium, only αB is detected in anterior cells, while αA and αB exist in a 1:3 ratio in equatorial cells; this ratio flips to 3:1 during secondary fiber cell differentiation and elongation123,152,153. Alpha-crystallins belong to the small heat shock protein family and have chaperone-like functions154, allowing these proteins to bind and sequester abnormal or unfolded proteins, preventing further protein aggregation. Small α-crystallin peptides have been explored for preventing protein aggregation-induced diseases, including cataracts, as described in a previous review155. However, increased or decreased chaperone-like activity of α-crystallins in mouse models demonstrates that either scenario leads to increased cataract severity and suggests that appropriate chaperone-like activity of α-crystallins is crucial for lens transparency156. Beta- and γ-crystallins belong to their own β/γ-crystallin protein family and are fiber cell specific; in mammals, there are 7 isoforms of β-crystallins that exist as dimers, tetramers, or higher order oligomers, and there are 7 isoforms of γ-crystallins that are monomers, as described in a previous review125. In addition to structural functions, β and γ-crystallins bind calcium ions and regulate calcium ion availability and reserves in lens fibers157,158,159,160,161.

Lens Cytoskeletal and Membrane Proteins

Lens epithelial and fiber cells have networks of F-actin, keratin or vimentin intermediate filaments, specialized beaded intermediate filaments, and microtubules, as described in previous reviews.162,163,164,165,166. In addition to functions in eye and lens development31,32,33,34, diverse F-actin networks in lens epithelial and fiber cells are important for lens transparency167,168,169,170,171,172. Recent work has shown that alteration of the F-actin network affects lens biomechanics173,174,175,176. Intermediate filaments composed of vimentin or keratin are only present in early stages of lens fiber cell differentiation or during embryonic development, respectively177,178,179,180,181; in contrast, all lens fibers have beaded intermediate filaments composed of heterodimers of filensin (aka CP95/CP115 and encoded by Bsfp1) and CP49 (aka phakinin and encoded by Bsfp2)182,183,184. The beaded appearance of these heterodimers is due to oligomers made up of CP49 and filensin decorating the filament core185,186 and the binding of α-crystallins along these specialized intermediate filaments187,188,189,190,191. The loss of either filensin or CP49 leads to complete loss of this network192,193,194,195. Disruption of vimentin intermediate filaments or beaded intermediate filaments causes cataracts in humans and animal models192,193,196,197,198,199,200,201,202,203,204, showing the importance of these cytoskeletal networks for lens transparency. Recent work suggests that microtubules are important for lens fiber cell elongation205,206 and formation of the organelle-free zone177.

Adherens junctions that interact with the actin cytoskeleton are important for lens formation207 and fiber cell differentiation. E-cadherin and N-cadherin are both expressed in lens epithelial cells208,209,210,211, and E-cadherin is switched off at the beginning of fiber cell differentiation212. N-cadherin is highly expressed in lens fiber cells and is enriched at the midpoints of the basal hexagonal foot of elongating fiber cells8,209. Loss of N-cadherin after primary fiber cell formation causes secondary fiber cell elongation disruption due to abnormal migration of the apical tips of differentiating fibers along the apical surface of anterior epithelial cells213. Disruption of Eph-ephrin bidirectional signaling in the lens causes defects in adherens junctions4,7,214,215,216.

Other major lens membrane proteins include aquaporins; connexins; MP20, as described in a previous review217; galectin 3; galectin-related interfiber protein (GRIFIN); integrins, as described in a previous review218; and secreted protein acidic and rich in cysteine (SPARC). Aquaporins and connexins are discussed in the next section. MP20 (aka MP17 or Lim2) is a lens-specific membrane protein with cell-cell adhesion functions85,219 that is abundant in fiber cells220,221; mutations in MP20 lead to cataracts222,223,224,225,226,227,228,229,230. Recent work has shown interactions between MP20 and galectin 3, another important cell-cell adhesion molecule231,232,233. GRIFIN, a lens specific isoform of galectin, is localized to fiber cell membranes and interacts with Pax6, crystallins, and cadherins234,235,236,237. Integrins are important linkers, between the extracellular matrix (ECM) and the cytoskeleton, that are required for normal lens development. Integrin isoforms expressed in the lens serve as receptors for capsule components like laminin, collagen, or fibronectin8,238,239,240,241,242,243,244,245. Each matrix component can interact with multiple integrins, leading to diverse signaling through the spatiotemporal expression of integrins during lens development and growth218. There is particular interest in understanding changes in TGFβ, integrins, and ECM components during epithelial-to-mesenchymal transition in residual lens epithelial cells after cataract surgery, leading to posterior capsule opacification, as described in a previous review218. SPARC, a cell-cell adhesion and proliferation molecule, is localized to the lens epithelium and is absent in differentiating fibers246. Loss of SPARC leads to cataracts246,247,248, and recent studies have shown that SPARC may have chaperone-like functions249, affects integrins and ECM proteins250,251,252, and influences the microcirculation pathway253.

The Microcirculatory Pathway of an Avascular Tissue

Due to a lack of blood supply, the fully formed lens generates its own microcirculation pathway to deliver nutrients and remove waste, as described in previous reviews254,255,256,257. An ionic current enters the lens at the anterior and posterior poles and exits at the equator258. The inward current relies on the movement of sodium into the extracellular spaces between lens cells at each pole down a concentration gradient generated by active transport, and the outward current is facilitated by gap junction channels on fiber cell membranes that are concentrated in near the lens equator to allow sodium ions to exit at the lens equator259. Equatorial epithelial and peripheral fiber cells have high expression of Na+/K+ ATPase pumps that actively exchange 3 sodium ions out of the cells for 2 potassium ions from the extralenticular environment260,261,262. The lens maintains high potassium concentration (135mM) and low sodium concentration (16mM) to set up the conditions to allow sodium to re-enter the lens at the poles, down the concentration gradient259,263. In addition to Na+/K+ ATPase, the ion cotransporter Na-K-2Cl cotransporter 1 (NKCC1) also helps to regulate the lens ion concentrations through activation by mechanosensitive channels, as described in a previous review264.

Gap junctions in the lens are composed of three connexins, connexin 43 (Cx43 or α1), Cx46 (or α3), and Cx50 (or α8)265,266. Cx43 is mainly expressed in lens epithelial cells267, and while initiation of fiber cell formation is normal in Cx43 KO lenses, the interface between epithelial and fiber cells has enlarged extracellular space and intracellular vacuoles, suggesting a function for Cx43 in osmotic balance268. Cx46 is concentrated in lens fiber cells, and Cx50 is present in both epithelial and fiber cells269. Cx23 is also expressed in fiber cells of mouse lenses, but not human lenses270,271,272,273. A dominant mutation in Cx23 causes fiber cell defects in mice270, but Cx23 KO lenses do not have any notable defects274. Six connexin subunits form a connexon or hemichannel, and a connexon on one cell docks with a connexon on the neighboring cell to form a gap junction, which creates a ~10 angstrom pore between the neighboring cells, allowing the exchange of small molecules, ions, and water275,276. Connexin hemichannels allow passage of materials between the intracellular cytoplasm and extracellular environment, as described in previous reviews277,278, and hemichannels are important for the microcirculation279, mechano-sensitive transport of nutrients and antioxidants280,281,282,283, and oxidative stress response284,285,286,287,288. Gap junctions congregate into large plaques on the fiber cell membrane; in the lens, the plaques can be micron-sized in diameter and are aligned along the long sides of neighboring fiber cells289. Loss of Cx46 in mouse lenses leads to dense nuclear cataracts due to blockage of the outflow pathway of the lens microcirculation290,291. The assembly and/or stability of large Cx46 plaques on the fiber cell membrane requires the F-actin and beaded intermediate filament networks289. Cx50 KO leads to microphthalmia, mild nuclear cataracts, and small lenses due to abnormal epithelial cell proliferation292,293. Loss of Cx50 affects the gating of the remaining Cx46 gap junction plaques in lens fiber cells139. Replacement of Cx50 with knock-in Cx46 expressed under the endogenous Cx50 locus (4 copies of Cx46) rescues cataracts due to loss of Cx50 and increases gap junction coupling between fibers, but these transparent knock-in lenses remain small142,294. Thus, Cx46 cannot replace the lens growth function of Cx50. The knock-in strategy has also been used to rescue nuclear cataracts caused by γB-crystallin mutant proteins, suggesting that increased gap junctional coupling can be a strategy for improved lens homeostasis and cataract prevention295.

The ionic flux generated by sodium ions is accompanied by water flow into lens cells through aquaporin channels259. Aquaporin channels are composed of Aqp1 in epithelial cells, while in fiber cells, Aqp0 (aka MIP) and Aqp5 make up water channels, depending on the maturity of the cells, as described in previous reviews264,296,297. Movement of water through gap junction channels generates a hydrostatic pressure gradient across the lens298,299, and this gradient maintains lens osmotic pressure through transient receptor potential vanilloid 1 (TRPV1) and TRPV4 mechanosensitive channels that increase and decrease, respectively, lens hydrostatic pressure299,300,301,302. Decreased zonular tension on the lens decreases hydrostatic pressure, activating TRPV1 and subsequently NKCC1 to increase ion concentration in the lens and driving water flow into the lens to restore normal hydrostatic pressure300,301. Conversely, increased zonular tension and lens volume activate TRPV4 and subsequently Na+/K+ ATPase to decrease lens ion concentration and thus decrease hydrostatic pressure300,301,302.

Essential nutrients and amino acids are transported into the lens via the microcirculation pathway303, and this transport is particularly important for OFZ fibers. Facilitative glucose transporters (GLUT) are found in lens epithelial and fiber cells; GLUT1 is expressed in both cell types, and GLUT3 is expressed in epithelial cells304,305,306,307. GLUT1 KO mice develop cataracts, suggesting that glucose uptake is required for lens transparency308. Glutathione (GSH), an important antioxidant for lens transparency309,310, is made in the lens and can be transported into the lens from the aqueous humor311,312,313,314,315. Cysteine, glutamate, and glycine are essential amino acids for GSH synthesis, and accumulation of these amino acids is present in the cortex and nuclear regions of the lens314,315. Age-related decrease in GSH synthesis or increased GSH use can lead to decreased GSH availability in the lens, especially in the nucleus316,317,318,319,320,321. Glutathione peroxidases (GPX) use GSH as a coenzyme to neutralize hydroperoxide, and recent work shows that ferroptosis due to toxic lipid peroxides can lead to cataracts due to disruption of GPX4322,323.

3D Lens Architecture and Biomechanics

The patterning of lens fibers into organized rows of hexagon-shaped cells originates from the patterning of equatorial epithelial cells into meridional rows (Figure 1A). The mechanisms that drive the organization of randomly packed and cobblestone-shaped equatorial epithelial cells into hexagon-shaped meridional row cells revolve around the actin cytoskeleton. Signaling of the receptor tyrosine kinase EphA2 is needed to drive the accumulation of F-actin at the vertices of hexagonal meridional row cells to promote cell organization7,324. Myosin IIA, a contractile protein that binds to F-actin, is also important for promoting hexagon cell shape8,325,326. It had long been theorized that this highly ordered packing of fiber cells is required for lens transparency, but mispacking due to loss of EphA27,324, mutations in myosin IIA325,326, or misshapen cells made during old age130 suggest that hexagonal cell packing is not required for transparency.

Fiber cells that stretch from the anterior to posterior poles can be several millimeters in length depending on the animal species and size of the lens327. Typically, fiber cells are only 4–7 µm in cross section327, and these long and skinny cells are held together by dynamic cell-cell interdigitations that form a 3D zipper between neighboring fiber cells, as described in a previous review328. Lens fiber cell interdigitations have complex patterns that change as the cells differentiate and mature from 1) peripheral newly formed fibers with small protrusions along the short sides and ball and socket protrusions along the long sides, 2) mature fiber cells undergoing organelle loss that have large paddles with small interlocking protrusions along the short sides, 3) perinuclear fibers with large interlocking protrusions along the short sides and tongue and groove interdigitations along the entire membrane, and 4) nuclear fibers with large protrusions along the short sides and globular membrane morphology along the entire membrane137,328,329,330,331,332,333,334,335,336,337,338,339 (Figure 1B). Recent work has provided direct evidence that interdigitations between lens fiber cells that depend on F-actin networks are important for tissue stiffness174, supporting a long-held hypothesis. Loss of ARVCF, a component of adherens junctions, leads to abnormal fiber cell interdigitations, enlarged extracellular space, and early onset cortical cataracts340. Defects in lens nucleus stiffness and size are correlated with changes in the tongue and groove interdigitations and delayed transition to the globular membrane morphology131.

Phylogenetic tree diagrams with evolutionary pathways in circular layout, visualizing lineage divergence.
Figure 3: Lens sutures patterning. Each colored line represents a single fiber cell. (A) Fiber cells in the embryonic human lens form a Y-suture. The Y-suture is mirrored at the anterior and posterior poles. (B) As the human lens continues to develop and grow, the suture will become more branched. A 4-branched suture is depicted here for simplicity. The suture pattern is offset between the two poles. Cartoons are not drawn to scale. Modeled after 45. Please click here to view a larger version of this figure.

The overall shape of the lens differs depending on the species, and fiber cell curvature and suture type are theorized to determine lens shape341,342. The suture is formed by the meeting of the tips of elongating fiber cells at the anterior and posterior poles, and the suture is mirrored between the two poles11,12,13,343 (Figure 3). In mouse lenses, the suture is Y-shaped, and in primate and human lenses, the suture starts out in a Y shape and becomes more branched with age11,12,45. Interestingly, the Y suture in mouse lenses constrains the elasticity or resilience of the lens after a mechanical load is removed, and branched sutures in KO lenses with disruption of Eph ephrin signaling are correlated with increased resilience344. The normal formation of the lens suture requires gap junction communication345, and age-related anterior cataracts in mouse lenses are the result of incomplete suture formation130.

Lens biomechanical properties can be influenced by a variety of molecular, cellular, and tissue factors, as described in a previous review16. Age-related increase in lens stiffness is thought to be a primary contributor to presbyopia346. In humans, when looking at distant objects, relaxation of the ciliary muscles stretches the zonular fibers attached to the capsule, resulting in the flattening of the lens1. When focusing on something up close, the ciliary muscle contracts allowing the zonules to relax, and the lens rounds up to focus light from the near object1. This process of accommodation requires lens biomechanical properties, ciliary muscle contraction, and zonular tension. With age, studies have shown little or no change in ciliary muscle contractility and zonular flexibility and tension347,348,349,350. Several studies have suggested that increased lens size and nucleus size and stiffness contribute to the overall stiffening of the whole lens with age26,351,352,353,354. However, studies of lens stiffness with age in mice suggest that there is little correlation between lens and nucleus size with whole lens stiffness130,132, indicating that other factors influence age-related lens stiffening. Recent work has shown that changes in cytoskeletal networks affect lens stiffness; loss of tropomyosin 3.5, an F-actin stabilizing protein, affects the composition and arrangement of F-actin networks at the membrane of fiber cells and decreases lens stiffness173. Similarly, spontaneous mutations in several inbred wild-type mouse lines lead to spontaneous KO of CP49192,355 and softer lenses356,357. Lens fiber cell membranes have unusually high cholesterol content358,359,360,361,362,363, which can regulate membrane elasticity364. Changes in membrane cholesterol content and binding of α-crystallins to the fiber cell membrane with age are theorized to increase lens stiffness365,366,367,368,369,370,371,372.

Challenges and Novel Methods for Studying the Lens

The 3D structure of the lens creates challenges for understanding cell-cell arrangement and for creating suitable in vitro models that recapitulate tissue architecture. While valuable insights on signaling and mutant protein localization have been elucidated using immortalized or primary culture cells, the isolated lens epithelial cells do not have the characteristic cuboidal morphology or have the same gene expression or cytoskeletal structures as native lens epithelial cells373. In vitro lentoid, as described in a previous review374 and lenslet models375 create fiber-like cells and balls of cells that resemble a mini lens, respectively. These models create a transparent lens-like structure that can be useful for rapid drug screening purposes, but neither model recapitulates normal fiber cell organization or the 3D structure of the lens. Many protocols have been developed for localizing proteins in lens tissue sections and immunostaining, and this method remains the most efficient way to understand whether proteins are expressed in specific cell compartments. However, tissue sectioning for histology and immunostaining can be difficult, especially in samples from older adult mammals, due to incomplete fixation of the lens137; and studying 3D structure in 2D sections removes details that are important for understanding the shape of cells, interactions between cells, and localization of proteins. While electron microscopy (EM) remains the gold standard for studying fiber cell shape, localizing proteins in EM samples remains challenging376,377,378. Recent work with flat mounts of the epithelial cell monolayer4,7,324,373, single fiber cell staining85,173,174,379, and whole lens imaging4,7,324,344,380,381 have revealed important information about cell-cell adhesions, lens biomechanics, and changing cytoskeletal networks in lens fibers.

Lens epithelial and fiber cells have different functions, transcriptomes, and proteomes, and previous studies comparing the different cell compartments were difficult because there is just a monolayer of epithelial cells covering the anterior hemisphere, limiting the amount of RNA or protein that can be collected without pooling many samples. Advancements in RNA extraction techniques, real-time PCR, and automated capillary electrophoresis Westerns have allowed gene and protein analysis of lens epithelial cell samples collected from one pair of mouse eyes130,132,373,382 or microdissected regions of the lens epithelium, cortical fibers, and nuclear fibers383. Single-cell transcriptomics allow in-depth profiling of lens cells from zebrafish embryos and larva and chick embryos384,385. These new methods open the door to reveal the molecular mechanisms that maintain each lens cell compartment during normal aging and pathology.

As the field advances, it is important to remember that mouse genetic background can play important roles in lens pathology386,387 and biomechanics355,356,357, and thus, littermate controls for experiments are crucial for data analysis. Mutant and KO mouse models provide a system for studying age-related cataracts and an increase in lens stiffness130,356,357,388,389,390,391,392,393,394,395,396,397, and due to the relatively short lifespan of mice, aging studies should be performed on old animals rather than extrapolating data from young animals.

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Conclusions

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Advances in technology for transcriptomics, proteomics, imaging, and biomechanical testing have improved our understanding of lens biology, physiology, and pathology. Our expanding knowledge about the differences between distinct populations of lens epithelial and fiber cells will be important for understanding changes during aging and the mechanisms for protein and cell longevity. There has been increased interest in developing pharmaceutical interventions for preventing or delaying cataracts and/or presbyopia and in th...

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Disclosures

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The authors have nothing to disclose.

Acknowledgements

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This work was funded by grant R01 EY032056 (to CC) from the National Eye Institute. The authors thank Isaiah J. Innis and Gryffin M. Flowers for their helpful comments.

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