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Visionary stem-cell therapies

Stem-cell engineering has allowed successful cornea transplantations in rabbits and the regeneration of transparent lens tissue in children, demonstrating the therapeutic potential of this approach. See Article p.323 & Letter p.376

To correctly refract light onto the retina at the back of the eye, the cornea and lens must remain transparent throughout life. Treatments for opacification of the cornea or lens involve donor transplants or artificial implants, respectively, but these procedures can be risky. Alternative strategies for treating such ocular disorders would be to transplant tissue grown in the laboratory from stem cells, or to coax resident stem cells to regenerate normal tissue in the body. Two papers in this issue, by Hayashi et al.1 (page 376) and Lin et al.2 (page 323), report work that advances these possibilities.

Blindness represents a great clinical and economic burden worldwide. Corneal transplantation has been the gold standard for restoring transparency since the first successful transplant in 1905 (ref. 3). However, despite the fact that corneal transplants are less likely to induce an immune response than transplants to other sites in the body, grafts can be rejected by the host body within five years4.

One promising strategy for avoiding rejection involves tissue engineering using the patient's own (autologous) cells. This approach has proved successful in treating people with ocular chemical burns, in whom autologous cells called limbal stem cells were used to replace the epithelial cells that make up the outermost layer of the cornea5,6. However, it is not always feasible to harvest sufficient stem cells to grow in the laboratory. As an alternative, the conversion of adult cells into induced pluripotent stem cells (iPSCs), which can develop into any cell type7, could supply enough cells for therapy.

During embryonic development, ocular tissue is formed from three tissue layers, one of which, the surface ectoderm, gives rise to the corneal epithelium and lens. Hayashi et al.1 grew human iPSCs in vitro under conditions that promoted the creation of a structure that they dubbed the self-formed ectodermal autonomous multi-zone (SEAM), which contained four defined concentric zones that in some ways mimicked the developing eye. The authors found that different SEAM zones contained cells with characteristics of the ocular surface ectoderm, the lens, the neuro-retina and the retinal pigment epithelium.

Blocking BMP signalling — an intracellular pathway required for the development of surface ectoderm cells — abolished zone 3 of the SEAM. Hayashi and colleagues tested the therapeutic potential of cells from this zone by harvesting the cells and selecting those that expressed genes characteristic of epithelial stem cells (Fig. 1a). The authors cultured transplantable sheets of corneal epithelium from the selected cells, and demonstrated that these sheets could restore a healthy corneal epithelium in rabbits in which corneal epithelial stem cells had been experimentally depleted.

Figure 1: Sight for sore eyes.

Opacity in the cornea or the lens of the eye can cause blindness, and current treatment strategies are less than ideal. a, To produce corneal sheets that could be transplanted into rabbits, Hayashi et al.1 cultured induced pluripotent stem cells (iPSCs, which can give rise to all body cell types) in conditions that promoted the development of a SEAM — a structure containing four distinct zones and resembling the embryonic eye. Isolation and further culture of epithelial stem cells from zone 3 of the SEAM successfully produced corneal sheets for transplantation. b, Opaque lenses are normally removed and replaced with artificial implants. Lin et al.2 devised a minimally invasive method for lens removal, which left lens epithelial stem cells (LECs) intact. These LECs regenerated the lens in rabbits, macaques and children, eliminating the need for implants.

Cataracts, which cause sight-threatening lens clouding8, are surgically treated by removing the lens from its supporting capsule and replacing it with an artificial intraocular lens (IOL). In children with congenital cataracts, a major cause of childhood blindness, the success of IOL implantation is limited9,10 — surgery can cause opacity in the line of vision and, because the eye is still growing, it is difficult to provide good vision with spectacles. Rather than attempting to create a living lens in vitro, Lin et al.2 investigated the possibility of regenerating a naturally transparent lens in the body.

The authors discovered that lens epithelial stem/progenitor cells (LECs) expressing the genes PAX6 and SOX2 self-renew and differentiate into lens fibre cells that can form a 3D transparent lens-like structure that refracts light. In mice, mutation of the stem-cell-maintenance gene Bmi-1, which is expressed in LECs, impaired LEC proliferation and induced cataract formation. These data led Lin et al. to reason that, by refining the technique for surgical cataract removal to minimize the damage done to LECs in situ, they could promote lens regeneration (Fig. 1b).

In rabbits, the authors' minimally invasive technique led to lens regeneration around seven weeks after surgery. The approach achieved similar results in macaques, in which lens regeneration took several months and no complications arose. Finally, the researchers performed a clinical trial, in which transparent lenses were regenerated in both eyes of 12 infants within 3 months, all without complication.

These two studies illustrate the remarkable regenerative and therapeutic potential of stem cells. Hayashi and colleagues' approach involved substantial in vitro cell manipulation to obtain a sheet of cultured corneal epithelium for transplantation. When considering the expense involved in following good manufacturing practices for cell therapies, the current protocol is unlikely to be economically viable. However, the real value of this research lies in the possibility that the SEAM model will facilitate the discovery of fundamental mechanisms that underlie the early development of each type of ocular tissue. Such an understanding might eventually enable in situ manipulation of stem-cell populations throughout the eye, as Lin et al. have elegantly shown to be achievable for the lens. Furthermore, lens regeneration might also turn out to be possible in ageing adults in whom LEC proliferation has declined — for example, research on the SEAM could identify small molecules able to stimulate such regeneration.

Whether either of the reported therapies will lead to cornea or lens transparency that can be maintained in the long term remains uncertain. However, these exciting studies take us away from simple therapies that involve like-for-like replacement of single mature cell types, and open up the possibility of therapeutic manipulation of the broader stem-cell environment in the eye.Footnote 1


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Correspondence to Julie T. Daniels.

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Daniels, J. Visionary stem-cell therapies. Nature 531, 309–310 (2016).

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