Ode to Stem Cells… and South Park?

by Andrew Sweeney

Stem cells might be controversial but they work, and their application in ophthalmology could herald tremendous benefits for patients. We examined one newly released study about how they could be used to heal the retina.

Have you ever seen the American animated TV show South Park ? The cartoon, which follows the exploits of four kids in the eponymous small Colorado town, is perhaps most famous for its free-flowing vulgarity and irreverence. However, don’t let this ostensibly juvenile approach fool you — the show is remarkable for its level of cultural and political insight, with its very rudeness allowing it to provide satirical commentary of a far higher degree of quality than any of its counterparts.

Take stem cells, for example. Years ago, during the early 2000s, stem cells had just begun to enter the consciousness of the general public, and the debate about their use, indeed — even their morality, was vicious. What was South Park’s approach? To take actor Christopher Reeve, a noted advocate for stem cell research after an accident left him paralyzed, and portray him gaining superpowers from every ‘cell’ he imbibed while being opposed at every turn by fellow actor Gene Hackman.

Throughout the episode, the show’s main characters would appear and say something along the lines of “Yeah… let’s stay out of this one.” In fact, that line would be the only appearance of all major characters throughout. It highlights how tempestuous the debate about stem cells was in those days, that the best joke South Park’s infamous creators could muster was that they wanted to stay out of the debate.

Popular awareness of stem cells has improved since then as has its acceptance by the medical community, and it’s not hard to understand why — they can provide remarkable benefits to patients. That’s because they are selfrenewing cells that can differentiate into specialized cell types and can develop into multiple specialized cells in a specific tissue. Pluripotent stem cells, i.e., embryonic stem cells (ESC) or induced pluripotent stem cells (iPSC), differentiate into cells of all three embryonic lineages.1

Since South Park’s commentary, it’s estimated that over one million patients worldwide have benefited from bone marrow transplantations performed for the treatment of leukemia, anemia, or immunodeficiencies. Skin stem cells are used to heal severe burns, while limbal stem cells can regenerate the damaged cornea. However, given their nature, there are numerous restrictions on ESCs, which is why adult, unipotent cells that differentiate only into one cell type are most commonly used.1

The existing and potential applications of stem cells in ophthalmology are remarkable, and it is no exaggeration to say that this research could revolutionize the field. According to one paper, applications in treating the cornea alone include chemical burns, corneal epitheliopathy, corneal laceration, dry eye disease, limbal stem cell deficiency, and keratoconus. Keratoplasty and keratoprosthesis, invasive treatment options for visual impairment that can result in extensive corneal scarring, could be replaced by stem cell therapy, and studies involving grafted autologous rabbit adipose stem cells on a poly lactic-co-glycolic acid have provided promising results.2

However, the benefits of stem cells in ophthalmology go beyond the cornea. There is evidence of their efficacy in retina treatment, too. One study found that the intravitreal injection of ADSCs in streptozotocin-induced diabetic rats correlated with fewer signs of early vascular derangement characteristic of diabetic retinopathy. Another reported that adiposestem-cell-derived exosomes ameliorated characteristic retinal degeneration following intraocular and subconjunctival administration among streptozotocin-induced diabetic rabbits.2

A study that could highlight how stem cells could be used to restore retinal function and eyesight, even partially, would, therefore, be a welcome development. Step forward a group of researchers based at Duke-NUS Medical School, the Singapore Eye Research Institute (both located in Singapore), and the Karolinska Institute in Stockholm, Sweden, who collectively thought: “Yeah, let’s NOT stay out of this one.” Their paper, Photoreceptor Laminin Drives Differentiation of Human Pluripotent Stem Cells to Photoreceptor Progenitors That Partially Restore Retina Function, 3 examines the idea outlined above.

The team of researchers came up with a novel approach to cultivate stem cells by utilizing pure laminin proteins that play a crucial role in the natural growth of human retinas. By exposing these cells to the laminins, they were able to guide their transformation into photoreceptor precursor cells that perform the crucial task of converting light into signals and transmitting them to the brain. Significant improvement in vision was subsequently observed in preclinical models when these cells were transplanted into damaged retinas.3

They observed that transplantation into 10 mice was able to protect the host photoreceptor outer nuclear layer (ONL) up to two weeks posttransplantation, as measured by fullfield electroretinogram. At four weeks post-transplantation, the engrafted cells were found to survive, mature, and associate with the host’s rod bipolar cells.3

Visual behavioral assessment using the water maze swimming test demonstrated visual improvement in the cell-transplanted rodents. At 20 weeks post-transplantation, the maturing engrafted cells were able to replace the loss of host ONL by extensive association with host bipolar cells and synapses.3

The researchers stated that by studying cell transcriptomic profiles and post-transplanted animal models, they demonstrated the absence of teratoma growth and partial improvement in vision. This suggested that the retina-specific laminin-based photoreceptor differentiation method may represent a safe approach for the treatment and management of retinal degenerative diseases. They also found that this method may also be useful for studying the mechanistic pathways involved in the progression of macular degeneration, possibly leading to the development of alternative therapeutic interventions.3

This news represents a welcome development in the utilization of stem cells in ophthalmology and could provide sight-saving treatment — so kudos! That’s what you get when you decide not to stay out of a specific issue à la South Park. And we can only hope for more stem cell developments, whether they be in the retina, cornea, or other areas of ophthalmology.

In South Park, instead of saying that someone killed Kenny, maybe next time they’ll be amazed at someone saving his sight instead – all thanks to stem cells…

1. Dulak J, Szade K, Szade A, et al. Adult Stem Cells: Hopes and Hypes of Regenerative Medicine. Acta A Biochim Pol. 2015;62(3):329-337.

2. Musa M, Zeppieri M, Enaholo ES, et al. Adipose Stem Cells in Modern-Day Ophthalmology. Clin Pract. 2023;13(1):230245.

3. Tay HG, Andre H, Guy CJ, et al. Photoreceptor Laminin Drives the Differentiation of Human Pluripotent Stem Cells to Photoreceptor Progenitors That Partially Restore Retina Function. Mol. Ther. 2023;31(3):825-846.