Tear Glands Grown in Lab Can Cry

A new study yields fascinating results that promise a possible solution to dry-eye disease and a step toward regenerative medicine.

This image shows a confocal image of a mouse lacrimal-gland organoid with the tear product Lcn2 labelled in red, showing that the organoids make tears. (Yorick Post, Hubrecht Institute)

(CN) — Trailblazing scientists have revealed a promising future in the search for treatment of dry-eye disease by using an innovative new technique to create miniature organs called organoids for testing.

This method, in which tissue obtained from stem cells is able to self-organize under optimal conditions in a lab, creates a three dimensional collection of cells known as organoids, capable of performing the same functions as an organ. 

According to a study published Tuesday in the journal Cell Stem Cell, organoids designed to replicate tear glands shed tears after being transplanted into mouse tear glands — promising significant advancement in the study of crying and dry-eye disease.

Lead author Hans Clevers from the Netherlands-based Hubrecht Institute and his colleagues offered evidence the organoids can produce tears and could potentially be used in human tear gland transplants in the distant future.

“We hope that scientists will use our model to identify new treatment options for patients with tear-gland disorders by either testing new drugs on a patient’s organoids or expanding healthy cells and, one day, using them for transplantation,” said Clevers.

The tear gland is a tiny organ located above each eye that produces the fluid for the tear film over our eyes. It keeps the eyes from drying out, covering the eyeball with moisture everytime we blink, while excess fluid is drained through the tear ducts into the nose.

When the tear system is not working properly or when it becomes irritated by wind, bright lights, allergies or other ailments, the eyes can become too wet or too dry — leading to overall discomfort. One such condition is known as dry-eye disease, which occurs when the tear system doesn’t produce enough tears or produces them in a way that the eye is unable to retain the moisture. Untreated, this can result in eye infections, inflammation, and damage to the surface of the eyes.

Dry-eye disease is also known as Sjögren’s syndrome, which is an autoimmune disorder that is accompanied by dry eyes and dry mouth. While scientists are aware of the symptoms, risk factors, and ways to avoid developing dry eyes, very little is known about what causes the condition or how to cure it. Currently the only avenues for recovery are eye drops, tear duct plugs to prevent excessive draining and surgery.

“What struck us is that at least 5% of the adult population is estimated to have dry-eye disease, which is most of the time related to a defect of tear production by the tear gland,” said co-author Yorick Post from the Hubrecht Institute. “But treatment options are limited because there was no complete understanding of the biology and no reliable, long-term in vitro model to study the tear gland.”

The team began their research to fill this gap by developing human and mouse lacrimal gland (tear gland) organoids, manipulating stem cells to form the miniature organs. Over the course of several months, the organoids grew in size and maturity, able to carry out all the necessary functions of the lacrimal-gland epithelium, which is the tissue in the gland that releases the tear fluid.

Once the organoid was fully matured, the team introduced noradrenaline to trigger the crying response, and they were pleased to see the organoid swell with tears.

“The challenge was to get the organoids to cry, as this is a hallmark of the lacrimal gland,” says co-author Marie Bannier-Hélaouët from the Hubrecht Institute. “We had to modify the cocktail of factors the organoids are grown in so that they would become the mature cells that we have in our tear glands and that are capable of crying.”

This video shows a human organoid swelling (i.e. crying) upon addition of adrenaline. (Marie Bannier-Hélaouët, Hubrecht Institute)

Hoping their research will prove fruitful in regenerative medicine, the authors put their organoids to the test. They placed human organoid cells into lacrimal glands from a mouse, and after two weeks they saw the formation of duct-like structures. The structures were there for about two months, and in that time the cells were seen organizing and multiplying, and even began producing tear proteins.

Furthermore, the researchers looked into the gene Pax6, which is responsible for much of the formation of tissues and organs in embryos. Pax6 is one of the main genes involved in eye development, and mutations within this gene are known to cause eye problems. 

To investigate the significance of this gene in adult tear glands, the team used CRISPR/Cas9 genome editing to remove Pax6 from the organoids, which prevented them from reaching maturity. The researchers believe Pax6 introduction will be a possible avenue for treatment as some patients with dry-eye syndrome lack the gene.

Additionally, the team also discovered some new details about the tear system in the lacrimal gland. Using single cell sequencing, they found that two cells present in the tear gland, ductal and acinar cells, produce different parts of tears.

Further research will be needed to test organoid transplant in treating dry-eye disease, which the researchers plan on testing in mouse models. They also hope to use this method to study Sjögren’s syndrome by testing the effects of introducing immune cells to the organoids.

“Patient-derived organoids open up new avenues to study lacrimal gland diseases in a personalized fashion,” Clevers said. “But there is still a long way to go before these mini-organoids can be used for regenerative therapies.”

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