Advancements in retinal organoid transplantation and stem cell therapies unveiled at APAO 2024
In recent years, there has been remarkable progress in retinal organoid transplantation and stem cell therapies, marking significant breakthroughs for addressing a range of ocular disorders—including retinitis pigmentosa and corneal nerve damage.
Recent advancements in retinal organoid transplantation and stem cell therapies offer promising prospects for treating eye conditions. At the 39th Congress of the Asia-Pacific Academy of Ophthalmology (APAO 2024) held recently in Bali, Indonesia, experts unveiled latest discoveries, offering insights into the potential of these breakthroughs.
Proliferative behavior of retinal organoid cells
According to Dr. Mandeep Singh (US), while we usually expect transplanted retinal organoid cells to survive, mature, and perform synaptogenesis and materials transfer, unexpected outcomes, such as migration and proliferation, could occur.
Dr. Singh and his team developed human retinal organoids (CRX:tdTomato+) and transplanted them into diseased mouse models while maintaining some cultured controls. After 4.5 months, the cells were analyzed for maturation, migratory, and proliferative behavior.
The findings of their study unveiled intriguing insights into the behavior of transplanted retinal organoid cells. “First, we found that donor cells have migrated from the subretinal space and over the optic nerve, crossing from one side of the retina to the other side,” shared Dr. Singh. Among these migrating cells are the surprising discovery of human astrocytes and brain and spinal-like cells (BSLCs).
With the identification of migratory cells, Dr. Singh and his team set out to investigate whether these cells proliferate and pose safety concerns for potential human treatments. To do so, they developed a proliferation scoring system based on the Gene Ontology classification.
Fortunately, the results of their investigation provided reassuring insights. “We found that migratory proliferating cells were rare in cultured organoids, and significantly fewer in transplanted organoids. These cells are mostly astrocytes and brain/spinal-like cells. Non-migratory proliferating cells are also rare and they are mostly retinal progenitor cells that remain in the subretinal space,” he said.
“In conclusion, in-vitro human micro-organogenesis can produce complex organoids that include migratory cells, which may influence therapeutic studies. Thankfully, transplanted organoids showed fewer proliferative cells than cultured controls, suggesting regulation by local factors. Generally, these data do not raise a safety concern for malignant cells in these specific conditions,” Dr. Singh assured.
Retinal organoid transplantation for RP
Next, Dr. Yasuhiko Hirami (Japan) presented cases where iPSC-derived retinal organoid sheets were safely transplanted into two patients with end-stage retinitis pigmentosa (RP).
The grafts remained stable for over two years, showing no signs of rejection after discontinuation of immunosuppressive drugs. One of the patients reported a suspected partial improvement in the full-field stimulus threshold (FST) test and fixation stability, although there were no changes in visual acuity, Humphrey perimetry, and multifocal electroretinogram (ERG).
“We observed rosette-like structures in the grafts in the optical coherence tomography (OCT) images at one year after transplantation, consistent with our previous animal studies. This may indicate the presence of photoreceptor rosettes, with further details expected to be revealed by adaptive optics camera or OCT,” Dr. Hirami explained.
Dr. Hirami and his team were planning the next-step clinical study, which would include the use of genetically modified retinal organoids aimed at enhancing functional integration.
Stem cell therapy for corneal nerve regeneration
Beyond providing corneal sensation, corneal nerves maintain the integrity of the ocular surface. Various factors can cause corneal nerve damage, including viral infection, surgical intervention, acoustic neuroma, longterm contact lens use, and diabetic mellitus.
Fortunately, stem cell therapy holds promise in regenerating corneal nerves. Dr. Chia-ying Tsai (Taiwan) explored the therapeutic potential of mesenchymal stem cells in corneal nerve regeneration.
In a study, Dr. Tsai and her team showed that intrastromal injection of adipocyte-derived mesenchymal stem cells (AD-MSCs) improved corneal nerve regeneration in rabbits through a confocal microscope.
They developed an animal model of corneal nerve damage using rabbits and administered (AD-MSCs) at the central cornea. The control group received placebo injections of phosphate-buffered saline (PBS).
“Fluorescence staining images indicated complete healing of corneal epithelial wound by day 7 in both groups. There were no neovascularization or corneal infections in both groups up to day 28, which affirmed the procedure’s safety. In vivo confocal microscope was utilized to assess nerve regeneration. The AD-MSC group began to show nerve budding as early as day 14, whereas this phenomenon was not observed in the control group on day 21. On day 28, immunofluorescence staining showed a more evident appearance of regenerated nerves at sub-basal and intra-epithelial areas of the ADMSC group,” Dr. Tsai explained.
Additionally, in a different study, Dr. Tsai and her team showed that corneal limbal stem cells (classified as multipotent stem cells) have neural potential. “The neural crest stem cells (NCSCs), which can be derived from human pluripotent stem cells, can differentiate into Schwann cells neurons for peripheral nerve regeneration,” she shared.
Editor’s Note: The 39th Congress of the Asia-Pacific Academy of Ophthalmology (APAO 2024) was held in Bali, Indonesia, from February 22 to 25. Reporting for this story took place during the event.
