The lacrimal gland organs produce a tear-like fluid (red).Credit: Yorick Post / Hubrecht Institute
Initially, it took a long time – up to a day – for the cells to cry. But with experience and a little stimulation, the researchers finally made them cry in just half an hour.
The tearful cultures, reported in Selstamsel on March 16 is the first ‘organoids’ of the lacrimal gland – three-dimensional assemblages of cells designed to look like miniature versions of organs. Organoid glands that produce tears can be used to study and eventually treat diseases that cause dry eyes, including an autoimmune condition called Sjögren’s syndrome.
“It is very promising,” said eye pathologist Geeta Vemuganti at the University of Hyderabad in India.
In addition to their role in displaying emotions, tears help to lubricate and protect the eye. Dry eyes can be painful, inflamed and prone to infection.
To study tear production, developmental biologist Hans Clever’s laboratory at Utrecht University Medical Center in the Netherlands has developed a way to grow tear gland cells as organoids. The group has found ways to grow a menagerie of organoids, including miniature livers, cervical cancer and snake venom glands.
Welling up
Tear glands, also known as tear glands, are a particular challenge to study, says Darlene Dartt, who studies tear production at Massachusetts Eye and Ear in Boston. The glands are located above each eyeball, behind the bony path of the eye, making it difficult to do biopsy. Samples, if researchers can get them, are often small, she says.
Clevers’ laboratory used their expertise to work out cultural conditions for cells from mouse and human tear glands. To stimulate tear production, they exposed their organoids to various chemicals, including the neurotransmitter norepinephrine, which transmits messages between nerve cells and glands.
Because the organoids do not have tubes, the tear production causes them to swell. “If there was a tube, there would be drops,” Clevers says. And when the team transplanted the organoids into mice, the compositions matured and developed channel-like structures that found proteins in tears.
The ‘crying’ organoids swell from tears.Credit: Marie Bannier-Hélaouët / Hubrecht Institute
The team hopes the cells can be used to study tear glands and to look for drugs that affect tear development. Clevers and his colleagues have already used CRISPR genome care to study the development of lacrimal glands, and found that a gene is called Pax6 is important to guide cells to assume a tear gland identity. Pax6 is a well-known regulator of eye development: which is the flight version of Pax6 on the leg of a fruit fly an eye will develop.
Clevers’ laboratory is working closely with Dutch physicist and television presenter Freek Vonk to study structures that look like tear glands in crocodiles. The team hopes to use the organoids to study ‘crocodile tears’, which the reptiles use to excrete salt.
Transplant potential
Organoids derived from human cells can eventually also provide material for transplants to replace diseased or damaged tear glands. Clevers’ group and its collaborators have developed salivary gland organelles that will be tested in clinical trials from the summer for people suffering from dry mouth, a condition that can cause tooth decay and problems with chewing and tasting.
These salivary gland trials can serve as a test basis to work out methods that can then be adapted for future tear gland transplants, Dartt says. Meanwhile, she says, the work Clevers’ team has done to characterize tear glands – including creating a detailed map-by-cell map of the structures and their organoids – has shown that the glands are more heterogeneous than previously appreciated can send researchers back to reinterpret old data. “It has implications for many studies.”