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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.

The authors have nothing to disclose.

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&#160;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.
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/70442/70442fig1.jpg" /> 
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 &#181;m. Modified from 16,328. <a href="https://www.jove.com/files/ftp_upload/70442/70442fig1large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

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&#8217;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&#8217;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.

the mammalian ocular lens in focus: development, anatomy, physiology, transparency, biomechanics, and age-related challenges

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

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.

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...

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.

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 ...

The ocular lens is a transparent and ellipsoid tissue in the anterior chamber of the eye. And many people think that the lens is just a crystal and not made of cells, but the lens is actually built of thousands of cells in a beautiful 3D architecture. The lens has some of the oldest cells in the body and the center most cells in the lens have been there since you were an embryo.And every day light passes through those cells so that you can see clearly. Fun fact, scientists isolated proteins from the center of lenses from Greenland sharks, and they were able to determine that the sharks were over 400 years old. During embryogenesis, the lens is initially a monolayer of epithelial cells on the surface ectoderm.This monolayer of epithelial cells is called the lens placode. And during development, the lens placode will start to invaginate and form a little pouch. And this pouch eventually pinches off into the lens vesicle, and it is a hollow sphere of the lens epithelial cells.And during further development, the posterior lens epithelial cells will elongate and fill the cavity of this hollow sphere to form the embryonic lens. The lens continues to grow throughout life by adding more la

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Indiana University.  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.

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

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